Combination of a β-lactam compound, probenecid, and valproic acid and use thereof

Abstract

The present disclosure relates to a combination of valproic acid or a pharmaceutically acceptable salt thereof, a β-lactam compound or a pharmaceutically acceptable salt thereof, and probenecid or a pharmaceutically acceptable salt thereof. The present disclosure also relates to methods of treating or preventing disease using this combination.

Description

[Technical Field]

[0001] Related Applications This application claims the benefit of and priority to U.S. Provisional Application No. 62 / 987,963, filed March 11, 2020, the entire contents of which are incorporated herein by reference. [Background technology]

[0002] background Beta-lactam compounds are a class of antibiotics that contain a beta-lactam ring in their molecular structure. They are used to treat diseases associated with Gram-positive and Gram-negative bacteria. Valproic acid (VPA) is a drug used primarily to treat patients with seizure disorders and, less frequently, other neurological disorders such as mania and migraine. Treatment of acute infections may require coadministration of valproic acid with beta-lactam compounds, including penem antibiotics. Clinically significant decreases in serum valproic acid concentrations have been reported in patients receiving carbapenem antibiotics (e.g., ertapenem, imipenem, and meropenem), potentially resulting in loss of seizure control. The mechanism of this interaction is poorly understood. Summary of the Invention

[0003] overview In some embodiments, the present disclosure provides a method of treating or preventing a disease, comprising administering to a subject in need thereof: a pharmaceutically effective amount of valproic acid or a pharmaceutically acceptable salt thereof; a pharmaceutically effective amount of a β-lactam compound or a pharmaceutically acceptable salt thereof, and A pharmaceutically effective amount of probenecid or a pharmaceutically acceptable salt thereof.

[0004] In some embodiments, the present disclosure provides a method of treating or preventing a disease in a subject receiving valproic acid or a pharmaceutically acceptable salt thereof, comprising administering to a subject in need thereof: a pharmaceutically effective amount of a β-lactam compound or a pharmaceutically acceptable salt thereof, and A pharmaceutically effective amount of probenecid or a pharmaceutically acceptable salt thereof.

[0005] In some embodiments, the present disclosure provides a method of treating or preventing a disease in a subject receiving valproic acid or a pharmaceutically acceptable salt thereof and a β-lactam compound or a pharmaceutically acceptable salt thereof, the method comprising administering to a subject in need thereof: A pharmaceutically effective amount of probenecid or a pharmaceutically acceptable salt thereof.

[0006] In some embodiments, the present disclosure provides a method of reducing or alleviating side effects in a subject being administered valproic acid or a pharmaceutically acceptable salt thereof and a β-lactam compound or a pharmaceutically acceptable salt thereof, comprising administering to a subject in need thereof: A pharmaceutically effective amount of probenecid or a pharmaceutically acceptable salt thereof.

[0007] In some embodiments, the present disclosure provides a combination for treating or preventing a disease, the combination comprising: a pharmaceutically effective amount of valproic acid or a pharmaceutically acceptable salt thereof; a pharmaceutically effective amount of a β-lactam compound or a pharmaceutically acceptable salt thereof, and A pharmaceutically effective amount of probenecid or a pharmaceutically acceptable salt thereof.

[0008] In some embodiments, the present disclosure provides a combination for treating or preventing a disease in a subject being administered valproic acid or a pharmaceutically acceptable salt thereof, the combination comprising: a pharmaceutically effective amount of a β-lactam compound or a pharmaceutically acceptable salt thereof, and A pharmaceutically effective amount of probenecid or a pharmaceutically acceptable salt thereof.

[0009] In some aspects, the present disclosure provides probenecid or a pharmaceutically acceptable salt thereof for treating or preventing a disease in a subject being administered valproic acid or a pharmaceutically acceptable salt thereof and a β-lactam compound or a pharmaceutically acceptable salt thereof.

[0010] In some aspects, the present disclosure provides probenecid or a pharmaceutically acceptable salt thereof for reducing or alleviating side effects in a subject being administered valproic acid or a pharmaceutically acceptable salt thereof and a β-lactam compound or a pharmaceutically acceptable salt thereof.

[0011] In some embodiments, the present disclosure provides a combination comprising: a pharmaceutically effective amount of valproic acid or a pharmaceutically acceptable salt thereof; a pharmaceutically effective amount of a β-lactam compound or a pharmaceutically acceptable salt thereof, and A pharmaceutically effective amount of probenecid or a pharmaceutically acceptable salt thereof.

[0012] In some embodiments, the present disclosure provides a pharmaceutical kit comprising: a pharmaceutically effective amount of valproic acid or a pharmaceutically acceptable salt thereof; a pharmaceutically effective amount of a β-lactam compound or a pharmaceutically acceptable salt thereof, and A pharmaceutically effective amount of probenecid or a pharmaceutically acceptable salt thereof.

[0013] In some embodiments, the present disclosure provides a pharmaceutical composition comprising: a pharmaceutically effective amount of valproic acid or a pharmaceutically acceptable salt thereof; a pharmaceutically effective amount of a β-lactam compound or a pharmaceutically acceptable salt thereof, and A pharmaceutically effective amount of probenecid or a pharmaceutically acceptable salt thereof.

[0014] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. As used herein, the singular also includes the plural unless the context clearly dictates otherwise. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present disclosure, suitable methods and materials are described below. All publications, patent applications, patents, and other references mentioned herein are incorporated by reference. References cited herein are not admitted to be prior art to the claimed invention. In case of conflict, the present specification, including definitions, will control. Furthermore, the materials, methods, and examples are illustrative only and not intended to be limiting. In the event of a conflict between the chemical structure and the name of a compound disclosed herein, the chemical structure shall control.

[0015] Other features and advantages of the present disclosure will be apparent from the following detailed description and claims. [Brief explanation of the drawings]

[0016] [Figure 1] FIG. 1 shows the mean (±standard deviation) plasma concentrations (μg / ml) of valproic acid when administered alone and in combination with sulopenem (intravenous formulation).

[0017] [Figure 2] FIG. 1 shows the mean (±standard deviation) plasma concentrations (μg / ml) of valproic acid when administered alone and in combination with sulopenem (oral formulation).

[0018] [Figure 3] FIG. 1 shows the mean (±standard deviation) plasma concentrations (μg / ml) of valproic acid when administered alone and in combination with sulopenem and probenecid (oral formulation). DETAILED DESCRIPTION OF THE INVENTION

[0019] Detailed Description In some embodiments, the present disclosure provides a method of treating or preventing a disease, comprising administering to a subject in need thereof: a pharmaceutically effective amount of valproic acid or a pharmaceutically acceptable salt thereof; a pharmaceutically effective amount of a β-lactam compound or a pharmaceutically acceptable salt thereof, and A pharmaceutically effective amount of probenecid or a pharmaceutically acceptable salt thereof.

[0020] In some embodiments, the present disclosure provides a method of treating or preventing a disease in a subject receiving valproic acid or a pharmaceutically acceptable salt thereof, comprising administering to a subject in need thereof: a pharmaceutically effective amount of a β-lactam compound or a pharmaceutically acceptable salt thereof, and A pharmaceutically effective amount of probenecid or a pharmaceutically acceptable salt thereof.

[0021] In some embodiments, the present disclosure provides a method of treating or preventing a disease in a subject receiving valproic acid or a pharmaceutically acceptable salt thereof and a β-lactam compound or a pharmaceutically acceptable salt thereof, the method comprising administering to a subject in need thereof: A pharmaceutically effective amount of probenecid or a pharmaceutically acceptable salt thereof.

[0022] In some embodiments, the present disclosure provides a method of reducing or alleviating side effects in a subject being administered valproic acid or a pharmaceutically acceptable salt thereof and a β-lactam compound or a pharmaceutically acceptable salt thereof, comprising administering to a subject in need thereof: A pharmaceutically effective amount of probenecid or a pharmaceutically acceptable salt thereof.

[0023] In some embodiments, the present disclosure provides a combination for treating or preventing a disease, the combination comprising: a pharmaceutically effective amount of valproic acid or a pharmaceutically acceptable salt thereof; a pharmaceutically effective amount of a β-lactam compound or a pharmaceutically acceptable salt thereof, and A pharmaceutically effective amount of probenecid or a pharmaceutically acceptable salt thereof.

[0024] In some embodiments, the present disclosure provides a combination for treating or preventing a disease in a subject being administered valproic acid or a pharmaceutically acceptable salt thereof, the combination comprising: a pharmaceutically effective amount of a β-lactam compound or a pharmaceutically acceptable salt thereof, and A pharmaceutically effective amount of probenecid or a pharmaceutically acceptable salt thereof.

[0025] In some aspects, the present disclosure provides probenecid or a pharmaceutically acceptable salt thereof for treating or preventing a disease in a subject being administered valproic acid or a pharmaceutically acceptable salt thereof and a β-lactam compound or a pharmaceutically acceptable salt thereof.

[0026] In some aspects, the present disclosure provides probenecid or a pharmaceutically acceptable salt thereof for reducing or alleviating side effects in a subject being administered valproic acid or a pharmaceutically acceptable salt thereof and a β-lactam compound or a pharmaceutically acceptable salt thereof.

[0027] Effect of the method In some embodiments, the administration reduces or alleviates a side effect.

[0028] In some embodiments, the administration reduces or alleviates the side effects of administering valproic acid or a pharmaceutically acceptable salt thereof and a β-lactam compound or a pharmaceutically acceptable salt thereof without administering probenecid or a pharmaceutically acceptable salt thereof.

[0029] In some embodiments, the side effect is mania, seizures, increased likelihood of seizures, decreased valproic acid levels, neuromotor disorders, or potential neuromotor disorders in the subject.

[0030] In some embodiments, the side effect is mania.

[0031] In some embodiments, the side effect is mania associated with bipolar disease and / or migraine.

[0032] In some embodiments, the side effect is seizures.

[0033] In some embodiments, the side effect is an increased likelihood of seizures.

[0034] In some embodiments, the side effect is a decrease in valproic acid levels in the subject.

[0035] In some embodiments, the side effect is a neurological movement disorder.

[0036] In some embodiments, the side effect is possible neuromotor impairment.

[0037] In some embodiments, the side effect is a seizure associated with administration of the β-lactam compound.

[0038] In some embodiments, the side effect is a seizure associated with co-administration of a beta-lactam compound and valproic acid.

[0039] In some embodiments, the side effect is an increased likelihood of seizures associated with administration of the β-lactam compound.

[0040] In some embodiments, the side effect is an increased likelihood of seizures associated with co-administration of a beta-lactam compound and valproic acid.

[0041] In some embodiments, the side effect is a decrease in valproic acid levels in the subject associated with the co-administration of a β-lactam compound. In some embodiments, the side effect is a neuromotor disorder associated with the administration of a β-lactam compound.

[0042] In some embodiments, the side effect is a neuromotor disorder associated with the co-administration of a beta-lactam compound and valproic acid.

[0043] In some embodiments, the side effect is the possibility of neuromotor disorders associated with the administration of a β-lactam compound.

[0044] In some embodiments, the side effect is the potential for neuromotor disorders associated with the co-administration of a β-lactam compound and valproic acid.

[0045] In some embodiments, administration results in a lower likelihood of seizures in the subject compared to comparable subjects being administered without probenecid or a pharmaceutically acceptable salt thereof.

[0046] In some embodiments, administration results in an elevated concentration of valproic acid in the subject compared to a comparable subject being administered without probenecid or a pharmaceutically acceptable salt thereof.

[0047] In some embodiments, administration results in a decreased likelihood of neuromotor impairment in the subject compared to comparable subjects being administered without probenecid or a pharmaceutically acceptable salt thereof.

[0048] In some embodiments, the administration results in a plasma concentration of valproic acid or a pharmaceutically acceptable salt thereof in a subject in need thereof having a higher area under the curve (AUC) within about 15 minutes, about 30 minutes, about 1 hour, about 2 hours, about 3 hours, about 6 hours, about 12 hours, about 18 hours, about 1 day, about 2 days, about 3 days, about 4 days, about 5 days, about 6 days, or about 7 days after administration, compared to a comparable subject receiving a β-lactam compound or a pharmaceutically acceptable salt thereof and valproic acid or a pharmaceutically acceptable salt thereof without probenecid or a pharmaceutically acceptable salt thereof.

[0049] In some embodiments, the administration provides an increase in blood cholesterol levels in a subject in need thereof by about 0.1% or more, about 0.25% or more, about 0.5% or more, about 0.75% or more, about 1% or more, about 2% or more, about 3% or more, about 4% or more, about 5% or more, about 6% or more, about 7% or more, about 8% or more, about 9% or more, about 10% or more, about 15% or more compared to a comparable subject receiving a beta-lactam compound or a pharmaceutically acceptable salt thereof and valproic acid or a pharmaceutically acceptable salt thereof without probenecid or a pharmaceutically acceptable salt thereof. or about 20% or more, about 25% or more, about 30% or more, about 40% or more, about 50% or more, about 60% or more, about 80% or more, about 100% or more, about 150% or more, about 200% or more, about 300% or more, about 400% or more, or about 500% or more higher in plasma concentration of valproic acid or a pharmaceutically acceptable salt thereof within about 15 minutes, about 30 minutes, about 1 hour, about 2 hours, about 3 hours, about 6 hours, about 12 hours, about 18 hours, about 1 day, about 2 days, about 3 days, about 4 days, about 5 days, about 6 days, or about 7 days after administration.

[0050] In some embodiments, the administration results in a plasma concentration of valproic acid or a pharmaceutically acceptable salt thereof in a subject in need thereof having a higher maximum plasma concentration (Cmax) within about 15 minutes, about 30 minutes, about 1 hour, about 2 hours, about 3 hours, about 6 hours, about 12 hours, about 18 hours, about 1 day, about 2 days, about 3 days, about 4 days, about 5 days, about 6 days, or about 7 days after administration, compared to a comparable subject receiving a β-lactam compound or a pharmaceutically acceptable salt thereof and valproic acid or a pharmaceutically acceptable salt thereof without probenecid or a pharmaceutically acceptable salt thereof.

[0051] In some embodiments, the administration results in a maximum plasma concentration (C) that is about 0.1% or more, about 0.25% or more, about 0.5% or more, about 0.75% or more, about 1% or more, about 2% or more, about 3% or more, about 4% or more, about 5% or more, about 6% or more, about 7% or more, about 8% or more, about 9% or more, about 10% or more, about 15% or more, about 20% or more, about 25% or more, about 30% or more, about 40% or more, about 50% or more, about 60% or more, about 80% or more, about 100% or more, about 150% or more, about 200% or more, about 300% or more, about 400% or more, or about 500% or more higher in a subject in need thereof compared to a comparable subject receiving a β-lactam compound or a pharmaceutically acceptable salt thereof and valproic acid or a pharmaceutically acceptable salt thereof without probenecid or a pharmaceutically acceptable salt thereof. max ) within about 15 minutes, about 30 minutes, about 1 hour, about 2 hours, about 3 hours, about 6 hours, about 12 hours, about 18 hours, about 1 day, about 2 days, about 3 days, about 4 days, about 5 days, about 6 days, or about 7 days after administration.

[0052] In some embodiments, administration results in a plasma concentration of valproic acid or a pharmaceutically acceptable salt thereof in a subject in need thereof having substantially the same area under the curve (AUC) within about 15 minutes, about 30 minutes, about 1 hour, about 2 hours, about 3 hours, about 6 hours, about 12 hours, about 18 hours, about 1 day, about 2 days, about 3 days, about 4 days, about 5 days, about 6 days, or about 7 days after administration compared to a comparable subject receiving valproic acid or a pharmaceutically acceptable salt thereof without the β-lactam compound, probenecid, or a pharmaceutically acceptable salt thereof.

[0053] In some embodiments, administration results in a plasma concentration of valproic acid or a pharmaceutically acceptable salt thereof in a subject in need thereof having an area under the curve (AUC) in the range of about 50% to about 150%, about 60% to about 140%, about 70% to about 130%, about 80% to about 120%, about 90% to about 110%, or about 95% to about 105% of the area under the curve (AUC) obtained in a comparable subject receiving valproic acid or a pharmaceutically acceptable salt thereof without the β-lactam compound, probenecid, or a pharmaceutically acceptable salt thereof, within about 15 minutes, about 30 minutes, about 1 hour, about 2 hours, about 3 hours, about 6 hours, about 12 hours, about 18 hours, about 1 day, about 2 days, about 3 days, about 4 days, about 5 days, about 6 days, or about 7 days after administration.

[0054] In some embodiments, administration results in a plasma concentration of valproic acid or a pharmaceutically acceptable salt thereof in a subject in need thereof having an area under the curve (AUC) that is about 50%, about 60%, about 70%, about 80%, about 90%, about 95%, about 98%, about 102%, about 105%, about 110%, about 115%, about 120%, about 125%, about 130%, about 140%, or about 150% of the area under the curve (AUC) obtained in a comparable subject receiving valproic acid or a pharmaceutically acceptable salt thereof without the β-lactam compound, probenecid, or a pharmaceutically acceptable salt thereof, within about 15 minutes, about 30 minutes, about 1 hour, about 2 hours, about 3 hours, about 6 hours, about 12 hours, about 18 hours, about 1 day, about 2 days, about 3 days, about 4 days, about 5 days, about 6 days, or about 7 days after administration.

[0055] In some embodiments, the administration results in substantially the same maximum plasma concentration (C) in a subject in need thereof compared to a comparable subject receiving valproic acid or a pharmaceutically acceptable salt thereof without the β-lactam compound, probenecid, or a pharmaceutically acceptable salt thereof. max ) within about 15 minutes, about 30 minutes, about 1 hour, about 2 hours, about 3 hours, about 6 hours, about 12 hours, about 18 hours, about 1 day, about 2 days, about 3 days, about 4 days, about 5 days, about 6 days, or about 7 days after administration.

[0056] In some embodiments, administration is performed in a subject in need thereof to a maximum plasma concentration (C) obtained in a comparable subject receiving valproic acid or a pharmaceutically acceptable salt thereof without the β-lactam compound, probenecid, or a pharmaceutically acceptable salt thereof. max ) in the range of about 50% to about 150%, about 60% to about 140%, about 70% to about 130%, about 80% to about 120%, about 90% to about 110%, or about 95% to about 105%. max ) within about 15 minutes, about 30 minutes, about 1 hour, about 2 hours, about 3 hours, about 6 hours, about 12 hours, about 18 hours, about 1 day, about 2 days, about 3 days, about 4 days, about 5 days, about 6 days, or about 7 days after administration.

[0057] In some embodiments, the administration is to administer to a subject in need thereof a maximal plasma concentration (C) of valproic acid or a pharmaceutically acceptable salt thereof without the β-lactam compound, probenecid, or a pharmaceutically acceptable salt thereof, compared to a comparable subject receiving valproic acid or a pharmaceutically acceptable salt thereof. max ) of about 50%, about 60%, about 70%, about 80%, about 90%, about 95%, about 98%, about 102%, about 105%, about 110%, about 115%, about 120%, about 125%, about 130%, about 140%, or about 150% of the maximum plasma concentration (C max ) within about 15 minutes, about 30 minutes, about 1 hour, about 2 hours, about 3 hours, about 6 hours, about 12 hours, about 18 hours, about 1 day, about 2 days, about 3 days, about 4 days, about 5 days, about 6 days, or about 7 days after administration.

[0058] Subjects and diseases to be treated In some embodiments, the subject in need thereof is an animal, hi some embodiments, the subject in need thereof is a human.

[0059] In some embodiments, the subject in need thereof is a human aged 18 years or older.

[0060] In some embodiments, the subject in need thereof is a human under the age of 18.

[0061] In some embodiments, the disease is associated with decreased gamma-aminobutyric acid (GABA) levels in the subject (e.g., in the subject's central nervous system). In some embodiments, the administration results in increased gamma-aminobutyric acid (GABA) levels in the subject (e.g., in the subject's central nervous system).

[0062] In some embodiments, the disease is associated with an increase or decrease in the population of one or more microorganisms (eg, bacteria) in a subject.

[0063] In some embodiments, the disease is associated with an increase in the population of one or more microorganisms (e.g., bacteria) in the subject. In some embodiments, the administration results in a decrease in the population of one or more microorganisms (e.g., bacteria) in the subject.

[0064] In some embodiments, the disease is associated with a decrease in the population of one or more microorganisms (e.g., bacteria) in the subject. In some embodiments, the administration results in an increase in the population of one or more microorganisms (e.g., bacteria) in the subject.

[0065] In some embodiments, the disease is associated with an increase or decrease in the population of one or more bacteria selected from Escherichia coli, Klebsiella pneumoniae, Proteus mirabilis, Enterobacter cloacae, Klebsiella oxytoca, Citrobacter freundii complex, Clostridium clostridioforme, Eubacterium lentum, Peptostreptococcus species, Bacteroides fragilis, Bacteroides distasonis, Bacteroides ovatus, Bacteroides thetaiotaomicron, Bacteroides uniformis, Bacteroides copricola, Prevotella copri, Porphyromonas asaccharolytica, and Prevotella vivia, or any organism of the following genera: Succinivibrio, Alistipes, Prevotella, Paraprevotella, Parabacteroides, and Odoribacter.

[0066] In some embodiments, the disease is associated with an increase or decrease in the population of one or more bacteria selected from Staphylococcus epidermidis, Streptococcus pneumoniae, Staphylococcus aureus, Streptococcus agalactiae, and Streptococcus pyogenes.

[0067] In some embodiments, the disease is associated with an increase or decrease in the population of one or more bacteria selected from Citrobacter freundii, Citrobacter koseri, Enterobacter aerogenes, Enterobacter cloacae, Haemophilus influenzae, Haemophilus parainfluenza, Klebsiella oxytoca, Moraxella catarrhalis, Morganella morganii, Proteus vulgaris, Providencia rettgeri, Providencia stuartii, and Serratia marcescens.

[0068] In some embodiments, the disease is associated with an increase or decrease in the population of one or more bacteria selected from Bacteroides vulgatus, Clostridium perfringens, and Fusobacterium species.

[0069] In some embodiments, the disease is associated with an infection. In some embodiments, the infection is a gram-negative bacterial infection. In some embodiments, the infection is a gram-positive bacterial infection.

[0070] In some embodiments, the infection is resistant to one or more antibiotics when administered without probenecid or a pharmaceutically acceptable salt thereof.

[0071] In some embodiments, the infection is resistant to one or more β-lactam compounds when administered without probenecid or a pharmaceutically acceptable salt thereof.

[0072] In some embodiments, the disease is uncomplicated urinary tract infection, complicated urinary tract infection, complicated intra-abdominal infection, uncomplicated intra-abdominal infection, pneumonia, otitis media, sinusitis, gonococcal urethritis, pelvic inflammatory disease, prostatitis, bone infection, joint infection, diabetic foot infection, and infectious diarrhea.

[0073] In some embodiments, the disease is associated with (e.g., caused by) an alteration in the microbiome in the subject.

[0074] In some embodiments, the disease is associated with (e.g., caused by) an alteration in the microbiome in a human subject.

[0075] In some embodiments, the disorder is mania.

[0076] In some embodiments, the disorder is bipolar disorder and / or mania associated with migraine.

[0077] In some embodiments, the disease is a neurodegenerative disease.

[0078] In some embodiments, the disease is amyotrophic lateral sclerosis, Parkinson's disease, Alzheimer's disease, schizophrenia, or Huntington's disease.

[0079] In some embodiments, the disease is Alzheimer's disease. It should be noted that probenecid has been shown to increase the concentration of β-lactam compounds in cerebrospinal fluid (Ralph G. Dacey and Merle A. Sande, Antimicrobial Agents and Chemotherapy 6:437-441 (1974)). Recently, the pathogenic bacterium Porphyromonas gingivalis has been found in the brain in association with pathological lesions associated with Alzheimer's disease (Dominy et al., Sci. Adv. 5:eaau3333 (2019)), and sulopenem is active against this bacterium (Lois M. Ednie and Peter C. Appelbaum, Antimicrobial Agents and Chemotherapy 53: 2163-2170 (2009)). Without wishing to be bound by theory, it is possible that β-lactam compounds (e.g., compound III-2b), when given with probenecid, may lead to more effective treatment of brain infections caused by this organism compared with treatment with sulopenem alone.

[0080] In some embodiments, the disease is cancer.

[0081] In some embodiments, the cancer is a solid cancer, such as ovarian cancer, breast cancer, head and neck cancer, renal cancer, bladder cancer, hepatocellular carcinoma, colorectal cancer, or lymphoma, or any combination thereof.

[0082] In some embodiments, the cancer is a sarcoma or carcinoma, such as fibrosarcoma, myxosarcoma, liposarcoma, chondrosarcoma, osteogenic sarcoma, chordoma, angiosarcoma, endothelial tumor, lymphangiosarcoma, lymphangioendothelial tumor, synovioma, mesothelioma, Ewing's tumor, leiomyosarcoma, rhabdomyosarcoma, colon carcinoma, pancreatic cancer, prostate cancer, squamous cell carcinoma, basal cell carcinoma, adenocarcinoma, sweat gland carcinoma, sebaceous gland carcinoma, papillary carcinoma, papillary adenocarcinoma, cystadenocarcinoma, medullary carcinoma, bronchogenic carcinoma, hepatocellular carcinoma, cholangiocarcinoma, choriocarcinoma, seminoma, embryonal carcinoma, Wilms' tumor, cervical cancer, testicular tumor, lung cancer, small cell lung carcinoma, epithelial carcinoma, glioma, astrocytoma, medulloblastoma, craniopharyngioma, ependymoma, pinealoma, hemangioblastoma, acoustic neuroma, oligodendroglioma, meningioma, melanoma, neuroblastoma, retinoblastoma.

[0083] In some embodiments, the cancer is a leukemia, such as acute lymphocytic leukemia and acute myeloid leukemia (myeloblastic, promyelocytic, myelomonocytic, monocytic, and erythroleukemia), or a chronic leukemia (chronic myeloid (granulocytic) leukemia and chronic lymphocytic leukemia).

[0084] In some embodiments, the cancer is polycythemia vera, lymphoma (Hodgkin's disease and non-Hodgkin's disease), multiple myeloma, Waldenstrom's macroglobulinemia, or heavy chain disease.

[0085] In some embodiments, the disease is inflammatory bowel disease.

[0086] In some embodiments, the inflammatory bowel disease is Crohn's disease, ulcerative colitis, indeterminate colitis, irritable bowel syndrome, microscopic colitis, diversion colitis, or Behcet's disease.

[0087] In some embodiments, the disease is uncomplicated urinary tract infection, complicated urinary tract infection, complicated intra-abdominal infection, acute bacterial prostatitis, community-acquired bacterial pneumonia, gonococcal urethritis, pelvic inflammatory disease, chronic bacterial prostatitis, Mycobacterium tuberculosis infection, non-tuberculous mycobacterial infection, bone and joint infection, acute and chronic sinusitis, diabetic foot infection, or infectious diarrhea (e.g., diarrhea due to Salmonella, Shigella, or Vibrio cholerae).

[0088] β-lactam compounds, probenecid, valproic acid In some embodiments, the β-lactam compound is a monobactam or a prodrug thereof.

[0089] In some embodiments, the β-lactam compound is aztreonam, tigemonam, carumonam, nocardicin A, a prodrug thereof, an analog thereof, or a derivative thereof.

[0090] In some embodiments, the β-lactam compound is a penem, carbapenem, clavam, or a prodrug thereof.

[0091] In some embodiments, the β-lactam compound is benzylpenicillin, benzathine benzylpenicillin, procaine benzylpenicillin, phenoxymethylpenicillin, propicillin, phenethicillin, azidocillin, clometocillin, penamecillin, cloxacillin (e.g., dicloxacillin or flucloxacillin), oxacillin, nafcillin, methicillin, amoxicillin, ampicillin (e.g., pivampicillin, hetacillin, bacampicillin, metaampicillin, talampicillin), epicillin, ticarcillin, carbenicillin, carindacillin, temocillin, piperacillin, azlocillin, mezlocillin, mecillinam (e.g., pivmecillinam), sulbenicillin, a pharmaceutically acceptable salt thereof, a prodrug thereof, an analog thereof, or a derivative thereof.

[0092] In some embodiments, the β-lactam compound is a penem, a carbapenem, or a prodrug thereof.

[0093] In some embodiments, the β-lactam compound is a thiopenem, oxypenem, aminopenem, alkylpenem, arylpenem, or a prodrug thereof.

[0094] In some embodiments, the β-lactam compound is ertapenem, an antipseudomonas carbapenem (e.g., doripenem, imipenem, meropenem), biapenem, panipenem, sulopenem, tebipenem, faropenem, a pharmaceutically acceptable salt thereof, a prodrug thereof, an analog thereof, or a derivative thereof.

[0095] In some embodiments, the β-lactam compound is a cephem, carbacephem, oxacephem, or a prodrug thereof.

[0096] In some embodiments, the beta-lactam compound is cefazolin, cephalexin, cefadroxil, cephapirin, cefazedone, cefazaflur, cephradine, cefroxadine, ceftezole, cephaloglycin, cephacetrile, cephalonium, cephaloridine, cephalothin, cefatrizine, cefaclor, cefotetan, cephamycins (e.g., cefoxitin, cefprozil, cefuroxime, cefuroxime axetil, cefamandole, cefminox, cefonicid, ceforanide, cefotiam, cefbuperazone, cefuzonam, cefmetazole), carbacephems (e.g., loracarbef), cefixime, ceftriaxone, antipseudomonal agents (e.g., ceftazidime, cefoperazone), cefdinir, cefcapene, cefdaloxime, ceftizoxime, cefmenoxime, cefotaxime, cefpiramide, cefpodoxime, ceftibuten, cefditoren, cefetamet, cefdidime, cefpimizole, cefsulodin, cefteram, ceftiolene, oxacephem (e.g., flomoxef, latamoxef), cefepime, cefozopran, cefpirome, cefquinome, ceftaroline fosamil, ceftolozane, ceftobiprole, ceftiofur, cefquinome, cefovecin, pharmaceutically acceptable salts thereof, prodrugs thereof, analogs thereof, or derivatives thereof.

[0097] In some embodiments, the β-lactam compound is thiopenem or a prodrug thereof.

[0098] In some embodiments, the β-lactam compound is a compound of formula (I): [ka] or a pharmaceutically acceptable salt thereof, a prodrug thereof, an analog thereof, or a derivative thereof, wherein R 1 is H or optionally substituted alkyl.

[0099] In some embodiments, the β-lactam compound is a compound of formula (Ia): [ka] a pharmaceutically acceptable salt thereof, a prodrug thereof, an analog thereof, or a derivative thereof.

[0100] In some embodiments, the β-lactam compound is a compound of formula (Ib): [ka] a pharmaceutically acceptable salt thereof, a prodrug thereof, an analog thereof, or a derivative thereof.

[0101] In some embodiments, R 1 is H.

[0102] In some embodiments, the β-lactam compound is a compound of formula (II): [ka] a pharmaceutically acceptable salt thereof, a prodrug thereof, an analog thereof, or a derivative thereof.

[0103] In some embodiments, the β-lactam compound is a compound of formula (IIa): [ka] a pharmaceutically acceptable salt thereof, a prodrug thereof, an analog thereof, or a derivative thereof.

[0104] In some embodiments, the β-lactam compound is a compound of formula (IIb): [ka] a pharmaceutically acceptable salt thereof, a prodrug thereof, an analog thereof, or a derivative thereof.

[0105] In some embodiments, R 1 is optionally substituted alkyl.

[0106] In some embodiments, the β-lactam compound is any one of the compounds of formula (III), (IIIa), and (IIIb): [ka] , a pharmaceutically acceptable salt thereof, a prodrug thereof, an analog thereof, or a derivative thereof, wherein R 2 is H or optionally substituted alkyl.

[0107] In some embodiments, the β-lactam compound is [ka] [ka] [ka] It is selected from the group consisting of a pharmaceutically acceptable salt thereof, a prodrug thereof, an analog thereof, or a derivative thereof.

[0108] In some embodiments, the β-lactam compound is [ka] [ka] [ka] It is selected from the group consisting of a pharmaceutically acceptable salt thereof, a prodrug thereof, an analog thereof, or a derivative thereof.

[0109] In some embodiments, the β-lactam compound is [ka] It is selected from a pharmaceutically acceptable salt thereof, a prodrug thereof, an analog thereof, or a derivative thereof.

[0110] In some embodiments, the β-lactam compound is [ka] is.

[0111] In some embodiments, the β-lactam compound has any one of formulas (IV), (IVa), and (IVb): [ka] [ka] [ka] or a pharmaceutically acceptable salt thereof, a prodrug thereof, an analog thereof, or a derivative thereof, wherein R 3 is H or optionally substituted alkyl.

[0112] In some embodiments, R 3 is a C2-C8 alkyl.

[0113] In some embodiments, R 3 is CH2CH3, CH2CH2CH3, or CH2CH(CH3)2 alkyl.

[0114] In some embodiments, the pharmaceutical salt of the β-lactam compound is a sodium salt, potassium salt, lithium salt, ammonium salt, calcium salt, magnesium salt, iron salt, zinc salt, copper salt, manganese salt, or aluminum salt.

[0115] It is understood that valproic acid has the following structure: [ka]

[0116] In some embodiments, the pharmaceutical salt of valproic acid is a sodium salt, potassium salt, lithium salt, ammonium salt, calcium salt, magnesium salt, iron salt, zinc salt, copper salt, manganese salt, or aluminum salt.

[0117] It is understood that probenecid (e.g., sold under the brand name Probalan) is of the following structure: [ka]

[0118] In some embodiments, the pharmaceutical salt of probenecid is a sodium salt, potassium salt, lithium salt, ammonium salt, calcium salt, magnesium salt, iron salt, zinc salt, copper salt, manganese salt, or aluminum salt.

[0119] Administration of valproic acid, beta-lactam compounds, and probenecid In some embodiments, valproic acid or a pharmaceutically acceptable salt thereof is administered one or more times daily, at about 0.1 mg, about 0.2 mg, about 0.3 mg, about 0.4 mg, about 0.5 mg, about 0.6 mg, about 0.7 mg, about 0.8 mg, about 0.9 mg, about 1 mg, about 2 mg, about 3 mg, about 4 mg, about 5 mg, about 6 mg, about 7 mg, about 8 mg, about 9 mg, about 10 mg, about 20 mg, about 30 mg, about 40 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, about 100 mg, about 120 mg, about 140 mg, about 150 mg, about 160 mg, about 170 mg, about 180 mg, about 190 mg, about 210 mg, about 220 mg, about 230 mg, about 240 mg, about 250 mg, about 260 mg, about 270 mg, about 280 mg, about 290 mg, about 300 mg, about 310 mg, about 320 mg, about 330 mg, about 340 mg, about 350 mg, about 360 mg, about 370 mg, about 380 mg, about 390 mg, about 400 mg, about 410 mg, about 420 mg, about 430 mg, about 440 mg, about 450 mg, about 460 mg, about 470 mg, about 480 mg, about 490 mg, about 500 mg, about 510 mg, about 520 mg, about 530 mg, about 540 mg, about 550 mg, about 560 mg, about 570 mg, about 580 mg, about The compound is administered at a daily dose of about 0 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, about 100 mg, about 200 mg, about 300 mg, about 400 mg, about 500 mg, about 600 mg, about 700 mg, about 800 mg, about 900 mg, about 1 g, about 2 g, about 3 g, about 4 g, about 5 g, about 6 g, about 7 g, about 8 g, about 9 g, about 10 g, about 20 g, about 30 g, about 40 g, or about 50 g.

[0120] In some embodiments, the valproic acid or a pharmaceutically acceptable salt thereof is administered once a day, twice a day, or three or more times a day.

[0121] In some embodiments, the valproic acid or a pharmaceutically acceptable salt thereof is administered continuously.

[0122] In some embodiments, the valproic acid or a pharmaceutically acceptable salt thereof is administered for about 2 days or more.

[0123] In some embodiments, the valproic acid or a pharmaceutically acceptable salt thereof is administered for about 2 days, about 3 days, about 4 days, about 5 days, about 6 days, about 7 days, about 14 days, or about 30 days.

[0124] In some embodiments, the valproic acid or a pharmaceutically acceptable salt thereof is administered with one or more drug-free days.

[0125] In some embodiments, the valproic acid or a pharmaceutically acceptable salt thereof is administered without a drug holiday.

[0126] In some embodiments, the valproic acid or a pharmaceutically acceptable salt thereof is administered enterally.

[0127] In some embodiments, the valproic acid or a pharmaceutically acceptable salt thereof is administered orally or rectally.

[0128] In some embodiments, the valproic acid or a pharmaceutically acceptable salt thereof is administered orally.

[0129] In some embodiments, the valproic acid or a pharmaceutically acceptable salt thereof is administered parenterally.

[0130] In some embodiments, the valproic acid or a pharmaceutically acceptable salt thereof is administered by injection (eg, intravenous infusion).

[0131] In some embodiments, the valproic acid or a pharmaceutically acceptable salt thereof is administered intravenously.

[0132] In some embodiments, the β-lactam compound or a pharmaceutically acceptable salt thereof is administered one or more times daily in a dose of about 0.1 mg, about 0.2 mg, about 0.3 mg, about 0.4 mg, about 0.5 mg, about 0.6 mg, about 0.7 mg, about 0.8 mg, about 0.9 mg, about 1 mg, about 2 mg, about 3 mg, about 4 mg, about 5 mg, about 6 mg, about 7 mg, about 8 mg, about 9 mg, about 10 mg, about 20 mg, about 30 mg, The compound is administered in a daily dose of about 40 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, about 100 mg, about 200 mg, about 300 mg, about 400 mg, about 500 mg, about 600 mg, about 700 mg, about 800 mg, about 900 mg, about 1 g, about 2 g, about 3 g, about 4 g, about 5 g, about 6 g, about 7 g, about 8 g, about 9 g, about 10 g, about 20 g, about 30 g, about 40 g, or about 50 g.

[0133] In some embodiments, the β-lactam compound or a pharmaceutically acceptable salt thereof is administered once a day, twice a day, or three or more times a day.

[0134] In some embodiments, the β-lactam compound or a pharmaceutically acceptable salt thereof is administered continuously.

[0135] In some embodiments, the β-lactam compound or a pharmaceutically acceptable salt thereof is administered for about 2 days or more.

[0136] In some embodiments, the β-lactam compound or a pharmaceutically acceptable salt thereof is administered for about 2 days, about 3 days, about 4 days, about 5 days, about 6 days, about 7 days, about 14 days, or about 30 days.

[0137] In some embodiments, the β-lactam compound or a pharmaceutically acceptable salt thereof is administered with one or more drug holidays.

[0138] In some embodiments, the β-lactam compound or a pharmaceutically acceptable salt thereof is administered without a drug holiday.

[0139] In some embodiments, the β-lactam compound or a pharmaceutically acceptable salt thereof is administered enterally.

[0140] In some embodiments, the β-lactam compound or a pharmaceutically acceptable salt thereof is administered orally or rectally.

[0141] In some embodiments, the β-lactam compound or a pharmaceutically acceptable salt thereof is administered orally.

[0142] In some embodiments, the β-lactam compound or a pharmaceutically acceptable salt thereof is administered parenterally.

[0143] In some embodiments, the β-lactam compound or a pharmaceutically acceptable salt thereof is administered by injection (eg, intravenous infusion).

[0144] In some embodiments, the β-lactam compound or a pharmaceutically acceptable salt thereof is administered intravenously.

[0145] In some embodiments, probenecid or a pharmaceutically acceptable salt thereof is administered one or more times daily in the amount of about 0.1 mg, about 0.2 mg, about 0.3 mg, about 0.4 mg, about 0.5 mg, about 0.6 mg, about 0.7 mg, about 0.8 mg, about 0.9 mg, about 1 mg, about 2 mg, about 3 mg, about 4 mg, about 5 mg, about 6 mg, about 7 mg, about 8 mg, about 9 mg, about 10 mg, about 20 mg, about 30 mg, about 40 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, about 100 mg, about 120 mg, about 140 mg, about 150 mg, about 160 mg, about 170 mg, about 180 mg, about 190 mg, about 210 mg, about 220 mg, about 230 mg, about 240 mg, about 250 mg, about 260 mg, about 270 mg, about 280 mg, about 290 mg, about 300 mg, about 310 mg, about 320 mg, about 330 mg, about 340 mg, about 350 mg, about 360 mg, about 370 mg, about 380 mg, about 390 mg, about 400 mg, about 410 mg, about 420 mg, about 430 mg, about 440 mg, about 450 mg, about 460 mg, about 470 mg, about 480 mg, about 490 mg, about 500 mg, about 510 mg, about 520 mg, about 530 mg, about 540 mg, about 550 mg, about 560 mg, about 570 mg, about 580 mg, about The compound is administered at a daily dose of about 0 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, about 100 mg, about 200 mg, about 300 mg, about 400 mg, about 500 mg, about 600 mg, about 700 mg, about 800 mg, about 900 mg, about 1 g, about 2 g, about 3 g, about 4 g, about 5 g, about 6 g, about 7 g, about 8 g, about 9 g, about 10 g, about 20 g, about 30 g, about 40 g, or about 50 g.

[0146] In some embodiments, probenecid or a pharmaceutically acceptable salt thereof is administered once a day, twice a day, or three or more times a day.

[0147] In some embodiments, the probenecid or a pharmaceutically acceptable salt thereof is administered continuously.

[0148] In some embodiments, the probenecid or a pharmaceutically acceptable salt thereof is administered for about 2 days or more.

[0149] In some embodiments, probenecid or a pharmaceutically acceptable salt thereof is administered for about 2 days, about 3 days, about 4 days, about 5 days, about 6 days, about 7 days, about 14 days, or about 30 days.

[0150] In some embodiments, probenecid or a pharmaceutically acceptable salt thereof is administered with one or more drug-free days.

[0151] In some embodiments, the probenecid or a pharmaceutically acceptable salt thereof is administered without a drug holiday.

[0152] In some embodiments, the probenecid or a pharmaceutically acceptable salt thereof is administered enterally.

[0153] In some embodiments, probenecid or a pharmaceutically acceptable salt thereof is administered orally or rectally.

[0154] In some embodiments, the probenecid or a pharmaceutically acceptable salt thereof is administered orally.

[0155] In some embodiments, the probenecid or a pharmaceutically acceptable salt thereof is administered parenterally.

[0156] In some embodiments, the probenecid or a pharmaceutically acceptable salt thereof is administered by injection (eg, intravenous infusion).

[0157] In some embodiments, probenecid or a pharmaceutically acceptable salt thereof is administered intravenously.

[0158] In some embodiments, the valproic acid or a pharmaceutically acceptable salt thereof, the β-lactam compound or a pharmaceutically acceptable salt thereof, and probenecid or a pharmaceutically acceptable salt thereof are administered simultaneously or sequentially.

[0159] In some embodiments, valproic acid or a pharmaceutically acceptable salt thereof and probenecid or a pharmaceutically acceptable salt thereof are administered simultaneously, sequentially, or alternatingly.

[0160] In some embodiments, the valproic acid or a pharmaceutically acceptable salt thereof and the β-lactam compound or a pharmaceutically acceptable salt thereof are administered simultaneously, sequentially, or alternately.

[0161] In some embodiments, the β-lactam compound or a pharmaceutically acceptable salt thereof and probenecid or a pharmaceutically acceptable salt thereof are administered simultaneously, sequentially, or alternately.

[0162] In some embodiments, the β-lactam compound or a pharmaceutically acceptable salt thereof and probenecid or a pharmaceutically acceptable salt thereof are administered simultaneously.

[0163] In some embodiments, the β-lactam compound or a pharmaceutically acceptable salt thereof and probenecid or a pharmaceutically acceptable salt thereof are administered sequentially.

[0164] In some embodiments, valproic acid or a pharmaceutically acceptable salt thereof, a β-lactam compound or a pharmaceutically acceptable salt thereof, and probenecid or a pharmaceutically acceptable salt thereof are administered simultaneously.

[0165] In some embodiments, the valproic acid or a pharmaceutically acceptable salt thereof and the β-lactam compound or a pharmaceutically acceptable salt thereof are administered simultaneously.

[0166] In some embodiments, valproic acid or a pharmaceutically acceptable salt thereof and probenecid or a pharmaceutically acceptable salt thereof are administered simultaneously.

[0167] In some embodiments, the β-lactam compound or a pharmaceutically acceptable salt thereof and probenecid or a pharmaceutically acceptable salt thereof are administered simultaneously.

[0168] In some embodiments, valproic acid or a pharmaceutically acceptable salt thereof and a β-lactam compound or a pharmaceutically acceptable salt thereof are administered simultaneously, followed by administration of probenecid or a pharmaceutically acceptable salt thereof.

[0169] In some embodiments, the valproic acid or a pharmaceutically acceptable salt thereof and the β-lactam compound or a pharmaceutically acceptable salt thereof are administered simultaneously after administration of probenecid or a pharmaceutically acceptable salt thereof.

[0170] In some embodiments, valproic acid or a pharmaceutically acceptable salt thereof and probenecid or a pharmaceutically acceptable salt thereof are administered simultaneously, followed by administration of the β-lactam compound or a pharmaceutically acceptable salt thereof.

[0171] In some embodiments, the valproic acid or a pharmaceutically acceptable salt thereof and probenecid or a pharmaceutically acceptable salt thereof are administered simultaneously after administration of the β-lactam compound or a pharmaceutically acceptable salt thereof.

[0172] In some embodiments, the β-lactam compound or a pharmaceutically acceptable salt thereof and probenecid or a pharmaceutically acceptable salt thereof are administered simultaneously, followed by administration of valproic acid or a pharmaceutically acceptable salt thereof.

[0173] In some embodiments, the β-lactam compound or a pharmaceutically acceptable salt thereof and probenecid or a pharmaceutically acceptable salt thereof are administered simultaneously after administration of valproic acid or a pharmaceutically acceptable salt thereof.

[0174] In some embodiments, the valproic acid or a pharmaceutically acceptable salt thereof, the β-lactam compound or a pharmaceutically acceptable salt thereof, and the probenecid or a pharmaceutically acceptable salt thereof are administered sequentially.

[0175] In some embodiments, the valproic acid or a pharmaceutically acceptable salt thereof, the probenecid compound or a pharmaceutically acceptable salt thereof, and the β-lactam or a pharmaceutically acceptable salt thereof are administered sequentially.

[0176] In some embodiments, the β-lactam compound or a pharmaceutically acceptable salt thereof, valproic acid or a pharmaceutically acceptable salt thereof, and probenecid or a pharmaceutically acceptable salt thereof are administered sequentially.

[0177] In some embodiments, the β-lactam compound or a pharmaceutically acceptable salt thereof, probenecid or a pharmaceutically acceptable salt thereof, and valproic acid or a pharmaceutically acceptable salt thereof are administered sequentially.

[0178] In some embodiments, the probenecid or a pharmaceutically acceptable salt thereof, the β-lactam or a pharmaceutically acceptable salt thereof, and the valproic acid or a pharmaceutically acceptable salt thereof are administered sequentially.

[0179] In some embodiments, probenecid or a pharmaceutically acceptable salt thereof, valproic acid or a pharmaceutically acceptable salt thereof, and a β-lactam or a pharmaceutically acceptable salt thereof are administered sequentially.

[0180] In some embodiments, the valproic acid or a pharmaceutically acceptable salt thereof, the β-lactam compound or a pharmaceutically acceptable salt thereof, and the probenecid or a pharmaceutically acceptable salt thereof are administered in close temporal proximity.

[0181] In some embodiments, the valproic acid or a pharmaceutically acceptable salt thereof and the β-lactam compound or a pharmaceutically acceptable salt thereof are administered closely in time.

[0182] In some embodiments, the valproic acid or a pharmaceutically acceptable salt thereof and the probenecid or a pharmaceutically acceptable salt thereof are administered closely in time.

[0183] In some embodiments, the β-lactam compound, or a pharmaceutically acceptable salt thereof, and probenecid, or a pharmaceutically acceptable salt thereof, are administered in close temporal proximity.

[0184] In some embodiments, the β-lactam compound or a pharmaceutically acceptable salt thereof is administered prior to administration of probenecid or a pharmaceutically acceptable salt thereof.

[0185] In some embodiments, probenecid or a pharmaceutically acceptable salt thereof is administered prior to administration of the β-lactam compound or a pharmaceutically acceptable salt thereof.

[0186] In some embodiments, the valproic acid or a pharmaceutically acceptable salt thereof, the β-lactam compound or a pharmaceutically acceptable salt thereof, and probenecid or a pharmaceutically acceptable salt thereof are administered by the same route.

[0187] In some embodiments, the valproic acid or a pharmaceutically acceptable salt thereof and the β-lactam compound or a pharmaceutically acceptable salt thereof are administered by the same route.

[0188] In some embodiments, valproic acid or a pharmaceutically acceptable salt thereof and probenecid or a pharmaceutically acceptable salt thereof are administered by the same route.

[0189] In some embodiments, the β-lactam compound or a pharmaceutically acceptable salt thereof and probenecid or a pharmaceutically acceptable salt thereof are administered by the same route.

[0190] In some embodiments, the valproic acid or a pharmaceutically acceptable salt thereof, the β-lactam compound or a pharmaceutically acceptable salt thereof, and the probenecid or a pharmaceutically acceptable salt thereof are administered by different routes.

[0191] In some embodiments, the valproic acid or a pharmaceutically acceptable salt thereof and the β-lactam compound or a pharmaceutically acceptable salt thereof are administered by different routes.

[0192] In some embodiments, the valproic acid or a pharmaceutically acceptable salt thereof and the probenecid or a pharmaceutically acceptable salt thereof are administered by different routes.

[0193] In some embodiments, the β-lactam compound or a pharmaceutically acceptable salt thereof and probenecid or a pharmaceutically acceptable salt thereof are administered by different routes.

[0194] In some embodiments, the valproic acid or a pharmaceutically acceptable salt thereof, the β-lactam compound or a pharmaceutically acceptable salt thereof, and the probenecid or a pharmaceutically acceptable salt thereof are administered enterally.

[0195] In some embodiments, the valproic acid or a pharmaceutically acceptable salt thereof and the β-lactam compound or a pharmaceutically acceptable salt thereof are administered enterally.

[0196] In some embodiments, valproic acid or a pharmaceutically acceptable salt thereof and probenecid or a pharmaceutically acceptable salt thereof are administered enterally.

[0197] In some embodiments, the probenecid or a pharmaceutically acceptable salt thereof and the β-lactam compound or a pharmaceutically acceptable salt thereof are administered enterally.

[0198] In some embodiments, the valproic acid or a pharmaceutically acceptable salt thereof is administered enterally.

[0199] In some embodiments, the probenecid or a pharmaceutically acceptable salt thereof is administered enterally.

[0200] In some embodiments, the β-lactam compound or a pharmaceutically acceptable salt thereof is administered enterally.

[0201] In some embodiments, the enteral administration is oral administration.

[0202] In some embodiments, the valproic acid or a pharmaceutically acceptable salt thereof, the β-lactam compound or a pharmaceutically acceptable salt thereof, and the probenecid or a pharmaceutically acceptable salt thereof are administered orally.

[0203] In some embodiments, the valproic acid or a pharmaceutically acceptable salt thereof and the β-lactam compound or a pharmaceutically acceptable salt thereof are administered orally.

[0204] In some embodiments, valproic acid or a pharmaceutically acceptable salt thereof and probenecid or a pharmaceutically acceptable salt thereof are administered orally.

[0205] In some embodiments, the probenecid or a pharmaceutically acceptable salt thereof and the β-lactam compound or a pharmaceutically acceptable salt thereof are administered orally.

[0206] In some embodiments, the valproic acid or a pharmaceutically acceptable salt thereof is administered orally.

[0207] In some embodiments, the probenecid or a pharmaceutically acceptable salt thereof is administered orally.

[0208] In some embodiments, the β-lactam compound or a pharmaceutically acceptable salt thereof is administered orally.

[0209] In some embodiments, an oral co-formulation comprising valproic acid or a pharmaceutically acceptable salt thereof, a β-lactam compound or a pharmaceutically acceptable salt thereof, and probenecid or a pharmaceutically acceptable salt thereof is administered.

[0210] In some embodiments, an oral co-formulation comprising valproic acid or a pharmaceutically acceptable salt thereof and a β-lactam compound or a pharmaceutically acceptable salt thereof is administered.

[0211] In some embodiments, an oral co-formulation comprising valproic acid or a pharmaceutically acceptable salt thereof and probenecid or a pharmaceutically acceptable salt thereof is administered.

[0212] In some embodiments, an oral co-formulation comprising a β-lactam compound or a pharmaceutically acceptable salt thereof and probenecid or a pharmaceutically acceptable salt thereof is administered.

[0213] In some embodiments, the oral co-formulation is administered to a subject one or more times daily.

[0214] In some embodiments, the oral co-formulation is administered to a subject once daily.

[0215] In some embodiments, a tablet containing valproic acid or a pharmaceutically acceptable salt thereof, a β-lactam compound or a pharmaceutically acceptable salt thereof, and probenecid or a pharmaceutically acceptable salt thereof is administered.

[0216] In some embodiments, a tablet containing valproic acid or a pharmaceutically acceptable salt thereof and a β-lactam compound or a pharmaceutically acceptable salt thereof is administered.

[0217] In some embodiments, a tablet containing valproic acid or a pharmaceutically acceptable salt thereof and probenecid or a pharmaceutically acceptable salt thereof is administered.

[0218] In some embodiments, a tablet containing a β-lactam compound or a pharmaceutically acceptable salt thereof and probenecid or a pharmaceutically acceptable salt thereof is administered.

[0219] In some embodiments, the tablet is a bilayer tablet comprising: a second layer comprising a β-lactam compound or a pharmaceutically acceptable salt thereof, and A first layer comprising probenecid or a pharmaceutically acceptable salt thereof.

[0220] In some embodiments, the first layer contains 20 mg to about 5 g, about 50 mg to about 2 g, about 80 mg to about 1 g, about 100 mg to about 900 mg, about 200 mg to about 800 mg, about 300 mg to about 700 mg, about 400 mg to about 600 mg, about 450 mg to about 550 mg, or about 480 mg to about 520 mg of probenecid or a pharmaceutically acceptable salt thereof.

[0221] In some embodiments, the second layer contains 20 mg to about 5 g, about 50 mg to about 2 g, about 80 mg to about 1 g, about 100 mg to about 900 mg, about 200 mg to about 800 mg, about 300 mg to about 700 mg, about 400 mg to about 600 mg, about 450 mg to about 550 mg, or about 480 mg to about 520 mg of a β-lactam compound (e.g., Compound III-2, Compound III-2a, or Compound III-2b) or a pharmaceutically acceptable salt thereof.

[0222] In some embodiments, the first layer comprises about 500±450 mg, about 500±400 mg, about 500±350 mg, about 500±300 mg, about 500±250 mg, about 500±200 mg, about 500±150 mg, about 500±100 mg, about 500±90 mg, about 500±80 mg, about 500±70 mg, about 500±60 mg, about 500±50 mg, about 500±45 mg, about 500±40 mg, about 500±35 mg, about 500±30 mg, about 500±25 mg, about 500±20 mg, about 500±15 mg, about 500±10 mg, or about 500±5 mg of probenecid or a pharmaceutically acceptable salt thereof.

[0223] In some embodiments, the second layer comprises about 500±400 mg, about 500±350 mg, about 500±300 mg, about 500±250 mg, about 500±200 mg, about 500±150 mg, about 500±100 mg, about 500±90 mg, about 500±80 mg, about 500±70 mg, about 500±60 mg, about 500±50 mg, about 500±45 mg, about 500±40 mg, about 500±35 mg, about 500±30 mg, about 500±25 mg, about 500±20 mg, about 500±15 mg, about 500±10 mg, or about 500±5 mg of a β-lactam compound (e.g., Compound III-2, Compound III-2a, or Compound III-2b) or a pharmaceutically acceptable salt thereof.

[0224] In some embodiments, the first layer comprises about 500 mg of probenecid or a pharmaceutically acceptable salt thereof.

[0225] In some embodiments, the second layer comprises about 500 mg of a β-lactam compound (eg, compound III-2, compound III-2a, or compound III-2b) or a pharmaceutically acceptable salt thereof.

[0226] In some embodiments, the bilayer tablet further comprises one or more pharmaceutical excipients.

[0227] In some embodiments, one or more of the pharmaceutical excipients is selected from cellulose, croscarmellose sodium, magnesium stearate, lactose monohydrate, and hydroxypropyl cellulose.

[0228] In some embodiments, the bilayer tablet is administered to a subject one or more times daily.

[0229] In some embodiments, the bilayer tablet is administered to a subject once daily.

[0230] In some embodiments, a tablet containing valproic acid or a pharmaceutically acceptable salt thereof is administered.

[0231] In some embodiments, a tablet containing a β-lactam compound or a pharmaceutically acceptable salt thereof is administered.

[0232] In some embodiments, a tablet containing probenecid or a pharmaceutically acceptable salt thereof is administered.

[0233] In some embodiments, the tablet is administered to the subject one or more times daily.

[0234] In some embodiments, the tablet is administered to the subject once daily.

[0235] In some embodiments, the valproic acid or a pharmaceutically acceptable salt thereof, the β-lactam compound or a pharmaceutically acceptable salt thereof, and the probenecid or a pharmaceutically acceptable salt thereof are administered in separate oral formulations.

[0236] In some embodiments, the tablets comprising valproic acid or a pharmaceutically acceptable salt thereof and the β-lactam compound or a pharmaceutically acceptable salt thereof are both administered in separate oral dosage forms.

[0237] In some embodiments, the tablets comprising valproic acid or a pharmaceutically acceptable salt thereof and probenecid or a pharmaceutically acceptable salt thereof are both administered in separate oral dosage forms.

[0238] In some embodiments, the tablets comprising the β-lactam compound or a pharmaceutically acceptable salt thereof and probenecid or a pharmaceutically acceptable salt thereof are both administered in separate oral dosage forms.

[0239] In some embodiments, the separate oral formulations are administered to the subject one or more times daily.

[0240] In some embodiments, the separate oral formulations are administered to the subject once daily.

[0241] In some embodiments, the valproic acid or a pharmaceutically acceptable salt thereof, the beta-lactam compound or a pharmaceutically acceptable salt thereof, and the probenecid or a pharmaceutically acceptable salt thereof are administered in separate tablets.

[0242] In some embodiments, the tablets comprising valproic acid or a pharmaceutically acceptable salt thereof and the beta-lactam compound or a pharmaceutically acceptable salt thereof are both administered in separate tablets.

[0243] In some embodiments, the tablets comprising valproic acid or a pharmaceutically acceptable salt thereof and probenecid or a pharmaceutically acceptable salt thereof are both administered in separate tablets.

[0244] In some embodiments, the β-lactam compound or a pharmaceutically acceptable salt thereof and probenecid or a pharmaceutically acceptable salt thereof are both administered in separate tablets.

[0245] In some embodiments, the tablet is administered to the subject one or more times daily.

[0246] In some embodiments, the tablet is administered to the subject once daily.

[0247] In some embodiments, the valproic acid or a pharmaceutically acceptable salt thereof, the β-lactam compound or a pharmaceutically acceptable salt thereof, and the probenecid or a pharmaceutically acceptable salt thereof are administered parenterally.

[0248] In some embodiments, the valproic acid or a pharmaceutically acceptable salt thereof and the β-lactam compound or a pharmaceutically acceptable salt thereof are administered parenterally.

[0249] In some embodiments, valproic acid or a pharmaceutically acceptable salt thereof and probenecid or a pharmaceutically acceptable salt thereof are administered parenterally.

[0250] In some embodiments, the β-lactam compound or a pharmaceutically acceptable salt thereof and probenecid or a pharmaceutically acceptable salt thereof are administered parenterally.

[0251] In some embodiments, the valproic acid or a pharmaceutically acceptable salt thereof is administered parenterally.

[0252] In some embodiments, the β-lactam compound or a pharmaceutically acceptable salt thereof is administered parenterally.

[0253] In some embodiments, the probenecid or a pharmaceutically acceptable salt thereof is administered parenterally.

[0254] In some embodiments, the parenteral administration is intravenous administration.

[0255] In some embodiments, the valproic acid or a pharmaceutically acceptable salt thereof, the β-lactam compound or a pharmaceutically acceptable salt thereof, and the probenecid or a pharmaceutically acceptable salt thereof are administered intravenously.

[0256] In some embodiments, the valproic acid or a pharmaceutically acceptable salt thereof and the β-lactam compound or a pharmaceutically acceptable salt thereof are administered intravenously.

[0257] In some embodiments, valproic acid or a pharmaceutically acceptable salt thereof and probenecid or a pharmaceutically acceptable salt thereof are administered intravenously.

[0258] In some embodiments, the β-lactam compound or a pharmaceutically acceptable salt thereof and probenecid or a pharmaceutically acceptable salt thereof are administered intravenously.

[0259] In some embodiments, the valproic acid or a pharmaceutically acceptable salt thereof is administered intravenously.

[0260] In some embodiments, the β-lactam compound or a pharmaceutically acceptable salt thereof is administered intravenously.

[0261] In some embodiments, probenecid or a pharmaceutically acceptable salt thereof is administered intravenously. In some embodiments, valproic acid or a pharmaceutically acceptable salt thereof, a β-lactam compound or a pharmaceutically acceptable salt thereof, and probenecid or a pharmaceutically acceptable salt thereof are administered in a co-formulation.

[0262] In some embodiments, the valproic acid or a pharmaceutically acceptable salt thereof and the β-lactam compound or a pharmaceutically acceptable salt thereof are administered in a co-formulation.

[0263] In some embodiments, the valproic acid or a pharmaceutically acceptable salt thereof and probenecid or a pharmaceutically acceptable salt thereof are administered in a co-formulation.

[0264] In some embodiments, the β-lactam compound or a pharmaceutically acceptable salt thereof and probenecid or a pharmaceutically acceptable salt thereof are administered in a co-formulation.

[0265] In some embodiments, the co-formulation is administered to a subject one or more times daily.

[0266] In some embodiments, the co-formulation is administered to a subject once daily.

[0267] In some embodiments, the co-formulation is an oral co-formulation (e.g., a tablet).

[0268] In some embodiments, the valproic acid or a pharmaceutically acceptable salt thereof, the β-lactam compound or a pharmaceutically acceptable salt thereof, and the probenecid or a pharmaceutically acceptable salt thereof are administered in separate formulations.

[0269] Exemplary Embodiments of the Method In some embodiments, valproic acid or a pharmaceutically acceptable salt thereof is administered at a dose of about 50 mg / day, about 100 mg / day, about 150 mg / day, about 200 mg / day, about 250 mg / day, about 300 mg / day, about 350 mg / day, about 400 mg / day, about 500 mg / day, about 1 g / day, about 2 g / day, about 3 g / day, about 4 g / day, or about 5 g / day.

[0270] In some embodiments, valproic acid or a pharmaceutically acceptable salt thereof is administered at a dose of 500±300 mg / day, 500±250 mg / day, 500±200 mg / day, 500±150 mg / day, 500±100 mg / day, 500±90 mg / day, 500±80 mg / day, 500±70 mg / day, 500±60 mg / day, 500±50 mg / day, 500±40 mg / day, 500±30 mg / day, 500±20 mg / day, 500±10 mg / day, 500±5 mg / day, 500±4 mg / day, 500±3 mg / day, 500±2 mg / day, 500±1 mg (e.g., about 500 mg / day).

[0271] In some embodiments, the β-lactam compound or a pharmaceutically acceptable salt thereof is administered at a dose of about 50 mg / day, about 100 mg / day, about 150 mg / day, about 200 mg / day, about 250 mg / day, about 300 mg / day, about 350 mg / day, about 400 mg / day, about 500 mg / day, about 1 g / day, about 2 g / day, about 3 g / day, about 4 g / day, or about 5 g / day.

[0272] In some embodiments, the beta-lactam compound or a pharmaceutically acceptable salt thereof is administered at a dose of 500±300 mg / day, 500±250 mg / day, 500±200 mg / day, 500±150 mg / day, 500±100 mg / day, 500±90 mg / day, 500±80 mg / day, 500±70 mg / day, 500±60 mg / day, 500±50 mg / day, 500±40 mg / day, 500±30 mg / day, 500±20 mg / day, 500±10 mg / day, 500±5 mg / day, 500±4 mg / day, 500±3 mg / day, 500±2 mg / day, 500±1 mg / day (e.g., about 500 mg / day).

[0273] In some embodiments, probenecid or a pharmaceutically acceptable salt thereof is administered at a dose of about 50 mg / day, about 100 mg / day, about 150 mg / day, about 200 mg / day, about 250 mg / day, about 300 mg / day, about 350 mg / day, about 400 mg / day, about 500 mg / day, about 1 g / day, about 2 g / day, about 3 g / day, about 4 g / day, or about 5 g / day.

[0274] In some embodiments, probenecid or a pharmaceutically acceptable salt thereof is administered at a dose of 500±300 mg / day, 500±250 mg / day, 500±200 mg / day, 500±150 mg / day, 500±100 mg / day, 500±90 mg / day, 500±80 mg / day, 500±70 mg / day, 500±60 mg / day, 500±50 mg / day, 500±40 mg / day, 500±30 mg / day, 500±20 mg / day, 500±10 mg / day, 500±5 mg / day, 500±4 mg / day, 500±3 mg / day, 500±2 mg / day, 500±1 mg / day (e.g., about 500 mg / day).

[0275] In some embodiments, valproic acid or a pharmaceutically acceptable salt thereof is administered at a dose of 500±300 mg / day, 500±250 mg / day, 500±200 mg / day, 500±150 mg / day, 500±100 mg / day, 500±90 mg / day, 500±80 mg / day, 500±70 mg / day, 500±60 mg / day, 500±50 mg / day, 500±40 mg / day, 500±30 mg / day, 500±20 mg / day, 500±10 mg / day, 500±5 mg / day, 500±4 mg / day, 500±3 mg / day, 500±2 mg / day, 500±1 mg / day (e.g., about 500 mg / day); The beta-lactam compound or a pharmaceutically acceptable salt thereof is administered at a dose of 500±300 mg / day, 500±250 mg / day, 500±200 mg / day, 500±150 mg / day, 500±100 mg / day, 500±90 mg / day, 500±80 mg / day, 500±70 mg / day, 500±60 mg / day, 500±50 mg / day, 500±40 mg / day, 500±30 mg / day, 500±20 mg / day, 500±10 mg / day, 500±5 mg / day, 500±4 mg / day, 500±3 mg / day, 500±2 mg / day, 500±1 mg / day (e.g., about 500 mg / day); and The probenecid or pharmaceutically acceptable salt thereof is administered at a dose of 500±300 mg / day, 500±250 mg / day, 500±200 mg / day, 500±150 mg / day, 500±100 mg / day, 500±90 mg / day, 500±80 mg / day, 500±70 mg / day, 500±60 mg / day, 500±50 mg / day, 500±40 mg / day, 500±30 mg / day, 500±20 mg / day, 500±10 mg / day, 500±5 mg / day, 500±4 mg / day, 500±3 mg / day, 500±2 mg / day, 500±1 mg / day (e.g., about 500 mg / day).

[0276] Combinations, Pharmaceutical Compositions, and Pharmaceutical Kits In some embodiments, the present disclosure provides a combination comprising: a pharmaceutically effective amount of valproic acid or a pharmaceutically acceptable salt thereof; a pharmaceutically effective amount of a β-lactam compound or a pharmaceutically acceptable salt thereof; and A pharmaceutically effective amount of probenecid or a pharmaceutically acceptable salt thereof.

[0277] In some embodiments, the present disclosure provides a pharmaceutical composition comprising: a pharmaceutically effective amount of valproic acid or a pharmaceutically acceptable salt thereof; a pharmaceutically effective amount of a β-lactam compound or a pharmaceutically acceptable salt thereof; and A pharmaceutically effective amount of probenecid or a pharmaceutically acceptable salt thereof.

[0278] In some embodiments, the present disclosure provides a pharmaceutical kit comprising: a pharmaceutically effective amount of valproic acid or a pharmaceutically acceptable salt thereof; a pharmaceutically effective amount of a β-lactam compound or a pharmaceutically acceptable salt thereof; and A pharmaceutically effective amount of probenecid or a pharmaceutically acceptable salt thereof.

[0279] definition As used herein, the terms "about" and "approximately" are used equivalently. Any numbers used in this application, with or without about / approximately, are meant to cover any normal variations understood by one of ordinary skill in the relevant art. In certain embodiments, the term "approximately" or "about" refers to a range of values ​​of 25%, 20%, 19%, 18%, 17%, 16%, 15%, 14%, 13%, 12%, 11%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, or less in either direction of the stated reference value, unless otherwise stated or apparent from the context (unless such number would exceed 100% of a possible value).

[0280] As used herein, "alkyl," "C1, C2, C3, C4, C5, or C6 alkyl," or "C1-C6 alkyl" is intended to include C1, C2, C3, C4, C5, or C6 straight-chain (straight-chain) saturated aliphatic hydrocarbon groups, and C3, C4, C5, or C6 branched saturated aliphatic hydrocarbon groups. For example, C1-C6 alkyl is intended to include C1, C2, C3, C4, C5, and C6 alkyl groups. Examples of alkyl include moieties having 1 to 6 carbon atoms, such as, but not limited to, methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl, t-butyl, n-pentyl, s-pentyl, or n-hexyl. In certain embodiments, a straight-chain or branched alkyl has 6 or fewer carbon atoms (e.g., C1-C6 for straight-chain, C3-C6 for branched-chain), and in other embodiments, a straight-chain or branched alkyl has 4 or fewer carbon atoms.

[0281] As used herein, "cycloalkyl" refers to a group having 3 to 30 carbon atoms (e.g., C3 to C4 12 , C3~C 10 , or C3-C8), a saturated or unsaturated non-aromatic hydrocarbon mono- or polycyclic (e.g., fused, bridged, or spirocyclic) system. Examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, 1,2,3,4-tetrahydronaphthalenyl, and adamantyl.

[0282] The term "heterocycloalkyl," as used herein, unless otherwise specified, refers to a saturated or unsaturated, non-aromatic 3-8 membered monocyclic ring system, 7-12 membered bicyclic ring system (fused, bridged, or spirocyclic), or 11-14 membered tricyclic ring system (fused, bridged, or spirocyclic), having one or more heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur (e.g., O, N, S, P, or Se), e.g., 1, or 1-2, or 1-3, or 1-4, or 1-5, or 1-6 heteroatoms, or e.g., 1, 2, 3, 4, 5, or 6 heteroatoms.Examples of heterocycloalkyl groups include, but are not limited to, piperidinyl, piperazinyl, pyrrolidinyl, dioxanyl, tetrahydrofuranyl, isoindolinyl, indolinyl, imidazolidinyl, pyrazolidinyl, oxazolidinyl, isoxazolidinyl, triazolidinyl, oxiranyl, azetidinyl, oxetanyl, thietanyl, 1,2,3,6-tetrahydropyridinyl, tetrahydropyranyl, dihydropyranyl, pyranyl, morpholinyl, and tetrahydrothiopyranyl. , 1,4-diazepanyl, 1,4-oxazepanyl, 2-oxa-5-azabicyclo[2.2.1]heptanyl, 2,5-diazabicyclo[2.2.1]heptanyl, 2-oxa-6-azaspiro[3.3]heptanyl, 2,6-diazaspiro[3.3]heptanyl, 1,4-dioxa-8-azaspiro[4.5]decanyl, 1,4-dioxaspiro[4.5]decanyl, 1-oxaspiro[4.5]decanyl, 1-azaspiro[4.5]decanyl, 3'H-spiro[cyclohexane-1,1'- isobenzofuran]-yl, 7'H-spiro[cyclohexane-1,5'-furo[3,4]-b]pyridin]-yl, 3'H-spiro[cyclohexane-1,1'-furo[3,4-c]pyridin]-yl, 3-azabicyclo[3.1.0]hexanyl, 3-azabicyclo[3.1.0]hexan-3-yl, 1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazolyl, 3,4,5,6,7,8-hexahydropyrido[4,3-d]pyrimidinyl, 4,5,6,7-tetrahydro-1H-pyra Examples of aromatic rings include 2-azaspiro[3.4-c]pyridinyl, 5,6,7,8-tetrahydropyrido[4,3-d]pyrimidinyl, 2-azaspiro[3.3]heptanyl, 2-methyl-2-azaspiro[3.3]heptanyl, 2-azaspiro[3.5]nonanyl, 2-methyl-2-azaspiro[3.5]nonanyl, 2-azaspiro[4.5]decanyl, 2-methyl-2-azaspiro[4.5]decanyl, 2-oxa-azaspiro[3.4]octanyl, 2-oxa-azaspiro[3.4]octan-6-yl, and the like. In the case of polycyclic non-aromatic rings, only one of the rings need be non-aromatic (e.g., 1,2,3,4-tetrahydronaphthalenyl or 2,3-dihydroindole).

[0283] As used herein, the term "optionally substituted alkyl" refers to an unsubstituted alkyl or an alkyl having specified substituents replacing one or more hydrogen atoms on one or more carbons of the hydrocarbon backbone. Such substituents may include, for example, alkyl, alkenyl, alkynyl, halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonate, phosphinate, amino (including alkylamino, dialkylamino, arylamino, diarylamino, and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl, and ureido), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfate, alkylsulfinyl, sulfonate, sulfamoyl, sulfonamido, nitro, trifluoromethyl, cyano, azido, heterocyclyl, alkylaryl, or aromatic or heteroaromatic moieties.

[0284] As used herein, the term "alkenyl" includes unsaturated aliphatic groups analogous in length and possible substitution to the alkyls described above, but which contain at least one double bond. For example, the term "alkenyl" includes straight-chain alkenyl groups (e.g., ethenyl, propenyl, butenyl, pentenyl, hexenyl, heptenyl, octenyl, nonenyl, decenyl) and branched alkenyl groups. In certain embodiments, a straight-chain or branched alkenyl group has six or fewer carbon atoms in its backbone (e.g., C2-C6 for straight chain, C3-C6 for branched chain). The term "C2-C6" includes alkenyl groups containing two to six carbon atoms. The term "C3-C6" includes alkenyl groups containing three to six carbon atoms.

[0285] As used herein, the term "alkynyl" includes unsaturated aliphatic groups analogous in length and possible substitution to the alkyls described above, but which contain at least one triple bond. For example, "alkynyl" includes straight-chain alkynyl groups (e.g., ethynyl, propynyl, butynyl, pentynyl, hexynyl, heptynyl, octynyl, nonynyl, decynyl) and branched alkynyl groups. In certain embodiments, a straight-chain or branched alkynyl group has six or fewer carbon atoms in its backbone (e.g., C2-C6 for straight chain, C3-C6 for branched chain). The term "C2-C6" includes alkynyl groups containing two to six carbon atoms. The term "C3-C6" includes alkynyl groups containing three to six carbon atoms. As used herein, the term "C2-C6 alkenylene linker" or "C2-C6 alkynylene linker" is intended to include C2, C3, C4, C5, or C6 chain (straight or branched) divalent unsaturated aliphatic hydrocarbon groups. For example, a C2-C6 alkenylene linker is intended to include C2, C3, C4, C5, and C6 alkenylene linker groups.

[0286] Other optionally substituted moieties (e.g., optionally substituted cycloalkyl, heterocycloalkyl, aryl, or heteroaryl) include both unsubstituted moieties and moieties having one or more of the specified substituents. For example, substituted heterocycloalkyls include those substituted with one or more alkyl groups, such as 2,2,6,6-tetramethyl-piperidinyl and 2,2,6,6-tetramethyl-1,2,3,6-tetrahydropyridinyl.

[0287] As used herein, the term "aryl" includes groups having aromatic character, including "conjugated" or polycyclic systems having one or more aromatic rings and no heteroatoms in the ring structure. Examples include phenyl, naphthalenyl, and the like.

[0288] The term "heteroaryl," as used herein, is intended to include stable 5-, 6-, or 7-membered monocyclic or 7-, 8-, 9-, 10-, 11-, or 12-membered bicyclic heteroaromatic rings, which consist of carbon atoms and one or more heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur, e.g., 1 or 1-2 or 1-3 or 1-4 or 1-5 or 1-6 heteroatoms, or e.g., 1, 2, 3, 4, 5, or 6 heteroatoms. The nitrogen atoms can be substituted or unsubstituted (i.e., N or NR, where R is H or other defined substituents). The nitrogen and sulfur heteroatoms can optionally be oxidized (i.e., N→O and S(O)). p , where p=1 or 2). It should be noted that the total number of S and O atoms in the aromatic heterocycle is not more than 1. Examples of heteroaryl groups include pyrrole, furan, thiophene, thiazole, isothiazole, imidazole, triazole, tetrazole, pyrazole, oxazole, isoxazole, pyridine, pyrazine, pyridazine, pyrimidine, and the like.

[0289] Furthermore, the terms "aryl" and "heteroaryl" include polycyclic aryl and heteroaryl groups, e.g., tricyclic, bicyclic, such as naphthalene, benzoxazole, benzodioxazole, benzothiazole, benzimidazole, benzothiophene, quinoline, isoquinoline, naphthyridine, indole, benzofuran, purine, benzofuran, deazapurine, indolizine.

[0290] A cycloalkyl, heterocycloalkyl, aryl, or heteroaryl ring may contain, at one or more ring positions (e.g., a ring carbon or a heteroatom such as N), a substituent as described above, such as alkyl, alkenyl, alkynyl, halogen, hydroxyl, alkoxy, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, alkylaminocarbonyl, aralkylaminocarbonyl, alkenylaminocarbonyl, alkylcarbonyl, arylcarbonyl, aralkylcarbonyl, alkenylcarbonyl, alkoxycarbonyl, aminocarbonyl, The aryl and heteroaryl groups can be substituted with aryl, alkylthiocarbonyl, phosphate, phosphonate, phosphinate, amino (including alkylamino, dialkylamino, arylamino, diarylamino, and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl, and ureido), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfate, alkylsulfinyl, sulfonato, sulfamoyl, sulfonamido, nitro, trifluoromethyl, cyano, azido, heterocyclyl, alkylaryl, or aromatic or heteroaromatic moieties. The aryl and heteroaryl groups can also be fused or bridged with alicyclic or heterocyclic rings that are not aromatic to form polycyclic systems (e.g., tetralin, methylenedioxyphenyl, e.g., benzo[d][1,3]dioxol-5-yl).

[0291] As used herein, the term "heterocycle" or "heterocyclic group" includes any ring structure (saturated, unsaturated, or aromatic) containing at least one ring heteroatom (e.g., 1 to 4 heteroatoms selected from N, O, and S). Heterocycles include heterocycloalkyl and heteroaryl. Examples of heterocycles include, but are not limited to, morpholine, pyrrolidine, tetrahydrothiophene, piperidine, piperazine, oxetane, pyran, tetrahydropyran, azetidine, and tetrahydrofuran.

[0292] Examples of heterocyclic groups include, but are not limited to, acridinyl, azocinyl, benzimidazolyl, benzofuranyl, benzothiofuranyl, benzothiophenyl, benzoxazolyl, benzoxazolinyl, benzthiazolyl, benztriazolyl, benztetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazolyl, carbazolyl, H4a-carbazolyl, carbolinyl, chromanyl, chromenyl, cinnolinyl, decahydroquinolinyl, 2H,6H-1,5,2-dithiazinyl, dihydrofuro[2,3- b] tetrahydrofuran, furanyl, furazanyl, imidazolidinyl, imidazolinyl, imidazolyl, 1H-indazolyl, indolenyl, indolinyl, indolizinyl, indolyl, 3H-indolyl, isatinoyl, isobenzofuranyl, isochromanyl, isoindazolyl, isoindolinyl, isoindolyl, isoquinolinyl, isothiazolyl, isoxazolyl, methylenedioxyphenyl (e.g., benzo[d][1,3]dioxol-5-yl), morpholinyl, naphthyridinyl, octahydroisoquinolinyl, oxazolyl Azolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,4-oxadiazol-5(4H)-one, oxazolidinyl, oxazolyl, oxindolyl, pyrimidinyl, phenanthridinyl, phenanthrolinyl, phenazinyl, phenothiazinyl, phenoxathinyl, phenoxazinyl, phthalazinyl, piperazinyl, piperidinyl, piperidonyl, 4-piperidonyl, piperonyl, pteridinyl, purinyl, pyranyl, pyrazinyl, pyrazolyl Dinyl, pyrazolinyl, pyrazolyl, pyridazinyl, pyridooxazole, pyridoimidazole, pyridothiazole, pyridinyl, pyridyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl, 2H-pyrrolyl, pyrrolyl, quinazolinyl, quinolinyl, 4H-quinolizinyl, quinoxalinyl, quinuclidinyl, tetrahydrofuranyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, tetrazolyl, 6H-1,2,5-thiadiazolyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,These include 4-thiadiazolyl, thianthrenyl, thiazolyl, thienyl, thienothiazolyl, thienoxazolyl, thienoimidazolyl, thiophenyl, triazinyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl, and xanthenyl.

[0293] As used herein, the term "substituted" means that any one or more hydrogen atoms on the designated atom are replaced with a selection from the described group, provided that the replacement does not exceed the normal valence of the described atom, and that the substitution results in a stable compound. When a substituent is oxo or keto (i.e., =0), two hydrogen atoms on the atom are replaced. Keto substituents are not present in aromatic moieties. As used herein, a ring double bond is a double bond formed between two adjacent ring atoms (e.g., C=C, C=N, or N=N). "Stable compound" and "stable structure" are meant to indicate a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture and formulation into an efficacious therapeutic agent.

[0294] When a bond to a substituent is shown to cross the bond connecting two atoms in a ring, such substituent may be bonded to any atom in the ring. When a substituent is listed without indicating the atom to which it is bonded to the remainder of the compound of a given formula, such substituent may be bonded through any atom in such formula. Combinations of substituents and / or variables are permissible, but only if such combinations result in stable compounds.

[0295] When any variable (e.g., R) occurs more than one time in any constituent or formula for a compound, its definition at each occurrence is independent of its definition at every other occurrence. Thus, for example, if a group is shown to be substituted with 0 to 2 R moieties, then that group may optionally be substituted with up to 2 R moieties, and R is independently selected from the definitions of R at each occurrence. Combinations of substituents and / or variables are permissible, but only if such combinations result in stable compounds.

[0296] As used herein, the term "hydroxy" or "hydroxyl" includes groups with an --OH or --O-- group.

[0297] As used herein, the term "halo" or "halogen" refers to fluoro, chloro, bromo, and iodo. The term "perhalogenated" generally refers to a moiety in which all hydrogen atoms are replaced with halogen atoms. The term "haloalkyl" or "haloalkoxyl" refers to an alkyl or alkoxyl substituted with one or more halogen atoms.

[0298] The term "carbonyl," as used herein, includes compounds and moieties which contain a carbon connected with a double bond to an oxygen atom. Examples of carbonyl-containing moieties include, but are not limited to, aldehydes, ketones, carboxylic acids, amides, esters, anhydrides, and the like.

[0299] The term "carboxyl" as used herein refers to -COOH or its C1-C6 alkyl esters.

[0300] As used herein, the term "acyl" includes moieties that contain the acyl group (RC(O)--) or a carbonyl group. As used herein, the term "substituted acyl" includes acyl groups in which one or more hydrogen atoms are replaced by, for example, an alkyl group, an alkynyl group, a halogen, a hydroxyl, an alkylcarbonyloxy, an arylcarbonyloxy, an alkoxycarbonyloxy, an aryloxycarbonyloxy, a carboxylate, an alkylcarbonyl, an arylcarbonyl, an alkoxycarbonyl, an aminocarbonyl, an alkylaminocarbonyl, a dialkylaminocarbonyl, an alkylthiocarbonyl, an alkoxyl, a phosphate, a phosphonate, a phosphinate, an amino (including alkylamino, dialkylamino, arylamino, diarylamino, and alkylarylamino), an acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl, and ureido), amidino, imino, a sulfhydryl, an alkylthio, an arylthio, a thiocarboxylate, a sulfate, an alkylsulfinyl, a sulfonato, a sulfamoyl, a sulfonamido, a nitro, a trifluoromethyl, a cyano, an azido, a heterocyclyl, an alkylaryl, or an aromatic or heteroaromatic moiety.

[0301] As used herein, the term "alkoxy" or "alkoxyl" includes substituted and unsubstituted alkyl, alkenyl, and alkynyl groups covalently linked to an oxygen atom. Examples of alkoxy or alkoxyl groups include, but are not limited to, methoxy, ethoxy, isopropyloxy, propoxy, butoxy, and pentoxy groups. Examples of substituted alkoxy groups include halogenated alkoxy groups. Alkoxy groups can be substituted with groups such as alkenyl, alkynyl, halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonate, phosphinate, amino (including alkylamino, dialkylamino, arylamino, diarylamino, and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl, and ureido), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfate, alkylsulfinyl, sulfonato, sulfamoyl, sulfonamido, nitro, trifluoromethyl, cyano, azido, heterocyclyl, alkylaryl, or aromatic or heteroaromatic moieties. Examples of halogen substituted alkoxy groups include, but are not limited to, fluoromethoxy, difluoromethoxy, trifluoromethoxy, chloromethoxy, dichloromethoxy, and trichloromethoxy.

[0302] The term "ether" or "alkoxy," as used herein, includes compounds or moieties which contain an oxygen bonded to two carbon atoms or heteroatoms. For example, the term includes "alkoxyalkyl," which refers to an alkyl, alkenyl, or alkynyl group covalently bonded to an oxygen atom which is covalently bonded to an alkyl group.

[0303] The term "ester," as used herein, includes compounds or moieties that contain a carbon or heteroatom bound to an oxygen atom that is bonded to the carbon of a carbonyl group. The term "ester" includes alkoxycarboxy groups, such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl, pentoxycarbonyl, and the like.

[0304] The term "thioalkyl," as used herein, includes compounds or moieties which contain an alkyl group bonded to a sulfur atom. Thioalkyl groups can be substituted with groups such as alkyl, alkenyl, alkynyl, halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, carboxylic acid, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, amino (including alkylamino, dialkylamino, arylamino, diarylamino, and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl, and ureido), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfate, alkylsulfinyl, sulfonato, sulfamoyl, sulfonamido, nitro, trifluoromethyl, cyano, azido, heterocyclyl, alkylaryl, or aromatic or heteroaromatic moieties.

[0305] The term "thiocarbonyl" or "thiocarboxy" as used herein includes compounds and moieties which contain a carbon connected with a double bond to a sulfur atom.

[0306] As used herein, the term "thioether" includes a moiety containing a sulfur atom bonded to two carbon or heteroatoms. Examples of thioethers include, but are not limited to, alkylthioalkyls, alkylthioalkenyls, and alkylthioalkynyls. The term "alkylthioalkyl" includes a moiety having an alkyl, alkenyl, or alkynyl group bonded to a sulfur atom which is bonded to an alkyl group. Similarly, the term "alkylthioalkenyl" refers to a moiety in which an alkyl, alkenyl, or alkynyl group is bonded to a sulfur atom which is covalently bonded to an alkenyl group, and "alkylthioalkynyl" refers to a moiety in which an alkyl, alkenyl, or alkynyl group is bonded to a sulfur atom which is covalently bonded to an alkynyl group.

[0307] As used herein, the term "amine" or "amino" refers to -NH. "Alkylamino" includes a group of compounds in which the nitrogen of -NH is bound to at least one alkyl group. Examples of alkylamino groups include benzylamino, methylamino, ethylamino, phenethylamino, and the like.

[0308] As used herein, the term "dialkylamino" includes groups in which the nitrogen of -NH is bonded to two alkyl groups. Examples of dialkylamino groups include, but are not limited to, dimethylamino and diethylamino.

[0309] As used herein, the terms "arylamino" and "diarylamino" include groups in which the nitrogen is bound to at least one or two aryl groups, respectively.

[0310] The terms "aminoaryl" and "aminoaryloxy" as used herein refer to aryl and aryloxy substituted with amino.

[0311] The term "alkylarylamino," "alkylaminoaryl," or "arylaminoalkyl," as used herein, refers to an amino group which is bound to at least one alkyl group and at least one aryl group.

[0312] The term "alkaminoalkyl," as used herein, refers to an alkyl, alkenyl, or alkynyl group bound to a nitrogen atom which is also bound to an alkyl group.

[0313] As used herein, the term "acylamino" includes groups in which the nitrogen is bound to an acyl group. Examples of acylamino include, but are not limited to, alkylcarbonylamino, arylcarbonylamino, carbamoyl, and ureido groups.

[0314] The term "amide" or "aminocarboxy" as used herein includes compounds or moieties which contain a nitrogen atom which is bound to the carbon of a carbonyl or a thiocarbonyl group.

[0315] As used herein, the term "alkaminocarboxy" includes alkyl, alkenyl, or alkynyl groups bound to an amino group which is bound to the carbon of a carbonyl or thiocarbonyl group.

[0316] As used herein, the term "arylaminocarboxy" includes aryl or heteroaryl moieties bound to an amino group which is bound to the carbon of a carbonyl or thiocarbonyl group.

[0317] As used herein, the terms "alkylaminocarboxy," "alkenylaminocarboxy," "alkynylaminocarboxy," and "arylaminocarboxy" include moieties in which alkyl, alkenyl, alkynyl, and aryl moieties are each bonded to a nitrogen atom which is in turn bonded to the carbon of a carbonyl group.

[0318] The amide can be substituted with a substituent such as a linear alkyl, a branched alkyl, a cycloalkyl, an aryl, a heteroaryl, or a heterocycle. The substituents on the amide group can be further optionally substituted.

[0319] Compounds of the present disclosure that contain nitrogen can be converted to N-oxides by treatment with an oxidizing agent (e.g., 3-chloroperoxybenzoic acid (mCPBA) and / or hydrogen peroxide) to provide other compounds of the present disclosure. Accordingly, all nitrogen-containing compounds shown and claimed may be converted to N-oxide derivatives (N→O or N) of the shown compounds and their N-oxide derivatives, where permitted by valence and structure. + -O - (which may be designated as N-hydroxy or N-alkoxy). Additionally, in other examples, nitrogens in the compounds of the present disclosure can be converted to N-hydroxy or N-alkoxy compounds. For example, N-hydroxy compounds can be prepared by oxidation of the parent amine with an oxidizing agent such as mCPBA. All nitrogen-containing compounds shown and claimed are considered to cover both the shown compound and its N-hydroxy (i.e., N—OH) and N-alkoxy derivatives, where permitted by valence and structure.

[0320] In this specification, the structural formula of a compound may conveniently represent a specific isomer, but the present disclosure encompasses all isomers, such as geometric isomers, optical isomers based on asymmetric carbons, stereoisomers, tautomers, etc., and it should be understood that not all isomers necessarily have the same level of activity. Furthermore, the compound represented by the formula may exist as a crystalline polymorph. It should be noted that any crystalline form, a crystalline mixture, or an anhydrous or hydrate thereof is included in the scope of the present disclosure.

[0321] As used herein, the term "isomer" means compounds that have identical molecular formulae but differ in the sequence of bonding of their atoms or the arrangement of their atoms in space. Isomers that differ in the arrangement of their atoms in space are called "stereoisomers." Stereoisomers that are not mirror images of one another are called "diastereomers," and stereoisomers that are non-superimposable mirror images of each other are sometimes called "enantiomers" or sometimes optical isomers. A mixture containing equal amounts of individual enantiomeric forms of opposite chirality is called a "racemic mixture."

[0322] As used herein, the term "chiral center" refers to a carbon atom bonded to four nonidentical substituents.

[0323] As used herein, the term "chiral isomer" refers to a compound having at least one chiral center. Compounds with more than one chiral center can exist as individual diastereomers or as a mixture of diastereomers called a "diastereomeric mixture." When one chiral center is present, a stereoisomer can be characterized by the absolute configuration (R or S) of that chiral center. Absolute configuration refers to the arrangement in space of the substituents attached to the chiral center. The substituents attached to the chiral center under consideration are ranked according to the Sequence Rule of Cahn, Ingold and Prelog (Cahn et al., Angew. Chem. Inter. Edit. 1966, 5, 385; errata 511; Cahn et al., Angew. Chem. 1966, 78, 413; Cahn and Ingold, J. Chem. Soc. 1951 (London), 612; Cahn et al., Experientia 1956, 12, 81; Cahn, J. Chem. Educ. 1964, 41, 116).

[0324] As used herein, the term "geometric isomer" refers to diastereomers whose existence results from hindered rotation about a double bond or a cycloalkyl linker (e.g., 1,3-cyclobutyl). These configurations are distinguished in names by the prefixes cis and trans, or Z and E, which indicate that the groups are on the same or opposite sides of a double bond in the molecule, according to the Cahn-Ingold-Prelog rules.

[0325] It should be understood that the compounds of the present disclosure may be depicted as different chiral or geometric isomers. When a compound has chiral or geometric isomeric forms, all isomeric forms are intended to be included within the scope of the present disclosure, and it should be understood that the naming of the compound does not exclude any isomeric form, and that not all isomers necessarily have the same level of activity.

[0326] It should be understood that the structures and other compounds discussed in this disclosure include all atropic isomers thereof. It should also be understood that not all atropic isomers necessarily have the same level of activity.

[0327] As used herein, the term "atropic isomer" refers to a type of stereoisomer in which the atoms of two isomers are arranged differently in space. Atropic isomers exist due to restricted rotation, which is caused by the prevention of rotation of large groups around a central bond. Such atropic isomers usually exist as mixtures, but recent advances in chromatography technology have made it possible to separate mixtures of two atropic isomers in certain cases.

[0328] As used herein, the term "tautomer" refers to one of two or more structural isomers that exist in equilibrium and are readily converted from one isomer to another. This conversion involves the formal migration of a hydrogen atom accompanied by the switching of adjacent conjugated double bonds. Tautomers exist as a mixture of tautomeric sets in solution. In solutions where tautomerization is possible, the tautomers reach chemical equilibrium. The exact ratio of tautomers varies depending on several factors, including temperature, solvent, and pH. The concept of tautomers that are interconvertible by tautomerization is called tautomerism. Of the various possible types of tautomerism, two are commonly observed: keto-enol tautomerism, in which a simultaneous electron and hydrogen atom shift occurs; and ring-shaped tautomerism, as exemplified by glucose, occurs when an aldehyde group (-CHO) in a sugar molecule reacts with one of the hydroxyl groups (-OH) in the same molecule to form a cyclic (ring-like) form, as exemplified by glucose.

[0329] It should be understood that the compounds of the present disclosure can be depicted as different tautomeric forms. When a compound has tautomeric forms, it should also be understood that all tautomeric forms are intended to be included within the scope of the present disclosure, and the naming of a compound does not exclude any tautomeric form. It will be understood that certain tautomers may have a higher level of activity than other tautomers.

[0330] As used herein, the terms "crystalline polymorph," "polymorph," or "crystalline form" refer to crystalline structures in which a compound (or a salt or solvate thereof) can crystallize in different crystal packing configurations, all of which have the same elemental composition. Different crystalline forms typically have different X-ray diffraction patterns, infrared spectra, melting points, density hardness, crystal shape, optical and electrical properties, stability, and solubility. Recrystallization solvent, crystallization rate, storage temperature, and other factors may cause one crystalline form to dominate. Crystalline polymorphs of a compound can be prepared by crystallization under different conditions.

[0331] It should be understood that the compounds of any formula described herein include the compounds themselves, as well as their salts and solvates, if applicable. For example, a salt can be formed between an anion on a substituted benzene compound and a positively charged group (e.g., amino). Suitable anions include chloride, bromide, iodide, sulfate, bisulfate, sulfamate, nitrate, phosphate, citrate, methanesulfonate, trifluoroacetate, glutamate, glucuronate, glutarate, malate, maleate, succinate, fumarate, tartrate, tosylate, salicylate, lactate, naphthalenesulfonate, and acetate (e.g., trifluoroacetate).

[0332] As used herein, the term "pharmaceutically acceptable anion" refers to an anion suitable for forming a pharmaceutically acceptable salt. Similarly, salts can also be formed between a cation on a substituted benzene compound and a negatively charged group (e.g., a carboxylate). Suitable cations include sodium, potassium, magnesium, calcium, and ammonium cations, such as tetramethylammonium. The substituted benzene compounds also include salts containing a quaternary nitrogen atom.

[0333] It should be understood that compounds of the present disclosure, for example, salts of the compounds, can exist in hydrated or unhydrated (anhydrous) form or as solvates with other solvent molecules. Non-limiting examples of hydrates include monohydrates, dihydrates, etc. Non-limiting examples of solvates include ethanol solvates, acetone solvates, etc.

[0334] The term "solvate" as used herein refers to a solvent addition form containing either a stoichiometric or non-stoichiometric amount of solvent. Some compounds tend to trap a fixed molar ratio of solvent molecules in a crystalline solid state, thus forming a solvate. When the solvent is water, the solvate formed is a hydrate. When the solvent is alcohol, the solvate formed is an alcoholate. A hydrate is formed by the combination of one or more water molecules with a molecule of a substance in which water maintains its molecular state as HO.

[0335] As used herein, the term "analog" refers to a chemical compound that is structurally similar to another compound but differs slightly in composition (such as in the replacement of one atom with an atom of a different element, or in the presence of a particular functional group, or in the replacement of one functional group with another functional group). Thus, an analog is a compound that is similar or equivalent in function and appearance to the reference compound, but differs in structure or origin.

[0336] As used herein, the term "derivative" refers to compounds that share a common core structure and are substituted with various groups as described herein.

[0337] The term "bioisostere" as used herein refers to a compound resulting from the exchange of an atom or group of atoms with another broadly similar atom or group of atoms. The goal of bioisosteric substitution is to create a new compound with similar biological properties as the parent compound. Bioisosteric substitution can be physicochemically or topologically based. Examples of carboxylic acid bioisosteres include, but are not limited to, acylsulfonimides, tetrazoles, sulfonates, and phosphonates. See, e.g., Patani and LaVoie, Chem. Rev. 96, 3147-3176, 1996.

[0338] It should be understood that the present disclosure is intended to include all isotopes of atoms present in the present compounds. Isotopes include atoms having the same atomic number but different mass numbers. By way of general example and without limitation, isotopes of hydrogen include tritium and deuterium, and isotopes of carbon include C-13 and C-14.

[0339] As used herein, the expressions "one or more of A, B, or C," "one or more of A, B, or C," "one or more of A, B, and C," "one or more of A, B, and C," "selected from the group consisting of A, B, and C," "selected from A, B, and C," etc. are used interchangeably and, unless otherwise indicated, refer to selection from the group of all, A, B, and / or C, i.e., one or more A, one or more B, one or more C, or any combination thereof.

[0340] As used herein, the term "substantially the same," as understood by one of ordinary skill in the art, refers to a value that is within any normal range above a reference value (e.g., a value in a comparable subject). In some embodiments, the term "substantially the same" refers to a value that is within a range of about 40% to about 160%, about 50% to about 150%, about 60% to about 140%, about 70% to about 130%, about 80% to about 120%, about 90% to about 110%, or about 95% to about 105% of the reference value (e.g., a value in a comparable subject). In some embodiments, the term "substantially the same" refers to a value that is about 50%, about 60%, about 70%, about 80%, about 90%, about 95%, about 98%, about 102%, about 105%, about 110%, about 115%, about 120%, about 125%, about 130%, about 140%, or about 150% of a reference value (e.g., a value in a comparable subject).

[0341] It should be understood that the present disclosure provides methods for the synthesis of compounds of any of the formulas described herein. The present disclosure also provides detailed methods for the synthesis of various disclosed compounds of the present disclosure according to the following schemes as well as those shown in the Examples.

[0342] Throughout the description, when a composition is described as having, including, or comprising particular components, it should be understood that the composition is also contemplated as consisting essentially of, or consisting of, the recited components. Similarly, when a method or process is described as having, including, or comprising particular recited process steps, the process also consists essentially of, or consists of, the recited processing steps. Furthermore, it should be understood that the order of steps or order of performing certain actions is immaterial so long as the invention remains operable. Moreover, two or more steps or actions may be performed simultaneously.

[0343] It should be understood that the synthetic processes of the present disclosure can tolerate a wide variety of functional groups, and thus variously substituted starting materials can be used. These processes generally provide the desired final compound at or near the end of the overall process, although in some cases it may be desirable to further convert the compound to a pharmaceutically acceptable salt thereof.

[0344] It should be understood that the compounds of the present disclosure can be prepared in a variety of ways using commercially available starting materials, compounds known in the literature, or readily prepared intermediates, by employing known standard synthetic methods and procedures that are known to, or will be apparent to, those skilled in the art in light of the teachings herein. Standard synthetic methods and procedures for the preparation of organic molecules and functional group transformations and manipulations can be obtained from the relevant scientific literature or from standard textbooks in the field. Without limitation to one or more sources, Smith, MB, March, J., March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, 5th edition, John Wiley & Sons: New York, 2001; Greene, TW, Wuts, PGM, Protective Groups in Organic Synthesis, 3rd edition, John Wiley & Sons: New York, 1999; R. Larock, Comprehensive Organic Transformations, VCH Publishers (1989); L. Fieser and M. Fieser, Fieser and Fieser's Reagents for Organic Synthesis, John Wiley and Sons (1994); and L. Paquette, ed., Encyclopedia of Reagents for Organic Synthesis, John Wiley and Sons (1995) (incorporated herein by reference) are useful and recognized reference texts of organic synthesis known to those skilled in the art.

[0345] Those skilled in the art will note that the order of certain steps, such as the introduction and removal of protecting groups, may be varied during the sequence of reactions and synthetic schemes described herein. Those skilled in the art will recognize that certain groups may require protection from reaction conditions through the use of protecting groups. Protecting groups can also be used to distinguish similar functional groups within a molecule. Lists of protecting groups and methods for introducing and removing these groups can be found in Greene, TW, Wuts, PGM, Protective Groups in Organic Synthesis, 3rd edition, John Wiley & Sons: New York, 1999.

[0346] Unless otherwise specified, any reference to a method of treatment should be understood to include the use of the compounds to provide treatment or prophylaxis as described herein, as well as the use of the compounds to prepare a medicament for treating or preventing such conditions. Treatment includes the treatment of humans or non-human animals, including, for example, rodents, and other disease models.

[0347] As used herein, the term "subject" is interchangeable with the term "subject in need thereof," both of which refer to a subject having a disease or at risk of developing a disease. "Subject" includes mammals. A mammal can be, for example, a human or a suitable non-human mammal, such as a primate, mouse, rat, dog, cat, cow, horse, goat, camel, sheep, or pig. A subject can also be a bird or poultry. In one embodiment, the mammal is a human.

[0348] As used herein, the term "comparable subject" refers to a subject having comparable parameters or in a comparable condition at the time of the compared subject (e.g., the treated subject). For example, a "comparable subject" may have a disease at the time of the compared subject or may be at increased risk of developing a disease at the time of the compared subject. In another example, a "comparable subject" may have one or more plasma pharmacokinetic parameters (e.g., C) for one or more drugs (e.g., a β-lactam compound, probenecid, or a combination thereof) at the time of the compared subject. maxIn some embodiments, a "comparable subject" may be a subject compared at a different time point, for example, a subject treated (e.g., by administering a combination of a β-lactam compound, probenecid, and / or valproic acid) may be subjected to the conditions of a "comparable subject" (e.g., administration of a β-lactam compound and probenecid without valproic acid) prior to treatment. In some embodiments, a "comparable subject" may be a subject compared at a different time point, for example, a subject treated (e.g., by administering a combination of a β-lactam compound, probenecid, and / or valproic acid) may be subjected to the conditions of a "comparable subject" (e.g., administration of a β-lactam compound and valproic acid without probenecid) prior to treatment. In some embodiments, a "comparable subject" may be a subject compared at a different time point, e.g., a subject treated (e.g., by administering a combination of a β-lactam compound, probenecid, and / or valproic acid) may be subjected to the conditions of a "comparable subject" (e.g., administration of valproic acid and probenecid without the β-lactam compound) prior to treatment. In some embodiments, a "comparable subject" may be a subject compared at a different time point, e.g., a subject treated (e.g., by administering a combination of a β-lactam compound and / or valproic acid) may be subjected to the conditions of a "comparable subject" (e.g., administration of a β-lactam compound without valproic acid) prior to treatment. In some embodiments, a "comparable subject" may be a subject compared at a different time point, e.g., a subject treated (e.g., by administering a combination of a β-lactam compound and / or probenecid) may be subjected to the conditions of a "comparable subject" (e.g., administration of a β-lactam compound without probenecid) prior to treatment. In some embodiments, a "comparable subject" may be a subject compared at a different time point, for example, a subject being treated (e.g., by administering a combination of probenecid and / or a β-lactam compound) may be subjected to the conditions of the "comparable subject" (e.g., administration of probenecid without the β-lactam compound) prior to treatment.In some embodiments, a "comparable subject" may be a subject compared at a different time point, for example, a subject treated (e.g., by administering a combination of probenecid and / or valproic acid) may be subjected to the conditions of a "comparable subject" (e.g., probenecid without valproic acid) before treatment. In some embodiments, a "comparable subject" may be a subject compared at a different time point, for example, a subject treated (e.g., by administering a combination of valproic acid and / or a β-lactam compound) may be subjected to the conditions of a "comparable subject" (e.g., administration of valproic acid without a β-lactam compound) before treatment. In some embodiments, a "comparable subject" may be a subject compared at a different time point, for example, a subject treated (e.g., by administering a combination of valproic acid and / or probenecid) may be subjected to the conditions of a "comparable subject" (e.g., valproic acid without probenecid) before treatment.

[0349] The term "treating" or "treat" as used herein describes the management and care of a patient for the purpose of combating a disease, condition, or disorder, and includes the administration of a compound of the present disclosure, or a pharmaceutically acceptable salt, polymorph, or solvate thereof, to alleviate the symptoms or complications of the disease, condition, or disorder, or to eliminate the disease, condition, or disorder. The term "treating" can also include treatment of an in vitro cell or animal model.

[0350] As used herein, the term "temporal proximity" refers to the administration of one therapeutic agent (e.g., a β-lactam, probenecid, or valproic acid compound disclosed herein) occurring within a time period before or after the administration of another therapeutic agent (e.g., a β-lactam, probenecid, or valproic acid compound), such that the therapeutic effect of one therapeutic agent overlaps with the therapeutic effect of the other therapeutic agent. In some embodiments, the therapeutic effect of one therapeutic agent completely overlaps with the therapeutic effect of the other therapeutic agent. In some embodiments, "temporal proximity" refers to the administration of one therapeutic agent occurring within a time period before or after the administration of another therapeutic agent, such that there is a synergistic effect between one therapeutic agent and the other therapeutic agent. "Temporal proximity" may vary depending on various factors, including, but not limited to, the age, sex, weight, genetic background, medical condition, medical history, and treatment history of the subject receiving the therapeutic agent; the disease or condition being treated or ameliorated; the therapeutic outcome being achieved; the dosage, frequency, and duration of administration of the therapeutic agent; the pharmacokinetics and pharmacodynamics of the therapeutic agent; and the route by which the therapeutic agent is administered. In some embodiments, "temporal proximity" means within 15 minutes, within 30 minutes, within 1 hour, within 2 hours, within 4 hours, within 6 hours, within 8 hours, within 12 hours, within 18 hours, within 24 hours, within 36 hours, within 2 days, within 3 days, within 4 days, within 5 days, within 6 days, within 1 week, within 2 weeks, within 3 weeks, within 4 weeks, within 6 weeks, or within 8 weeks. In some embodiments, multiple administrations of one therapeutic agent can be administered in temporal proximity to a single administration of another therapeutic agent. In some embodiments, temporal proximity can vary during a treatment cycle or dosing regimen.

[0351] The compounds of the present disclosure, or pharmaceutically acceptable salts, polymorphs, or solvates thereof, can or may be used to prevent the associated disease, condition, or disorder, or to identify suitable candidates for such purposes.

[0352] As used herein, the terms "preventing," "prevent," or "protect against" refer to reducing or eliminating the onset of symptoms or complications of such disease, condition, or disorder.

[0353] Those skilled in the art should understand that for detailed descriptions of known techniques discussed herein or equivalent techniques, they can refer to general references, including Ausubel et al., Current Protocols in Molecular Biology, John Wiley and Sons, Inc. (2005); Sambrook et al., Molecular Cloning, A Laboratory Manual (3rd edition), Cold Spring Harbor Press, Cold Spring Harbor, New York (2000); Coligan et al., Current Protocols in Immunology, John Wiley & Sons, NY; Enna et al., Current Protocols in Pharmacology, John Wiley & Sons, NY; Fingl et al., The Pharmacological Basis of Therapeutics (1975), Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, PA, 18th edition (1990); Mandell et al., Principles and Practice of Infectious Diseases, Saunders Publishing (8th edition, 2014). Of course, these documents may also be consulted when making or using aspects of the present disclosure.

[0354] It should be understood that the present disclosure also provides pharmaceutical compositions comprising any of the compounds described herein in combination with at least one pharmaceutically acceptable excipient or carrier.

[0355] As used herein, the term "pharmaceutical composition" refers to a formulation containing a compound of the present disclosure in a form suitable for administration to a subject. In one embodiment, the pharmaceutical composition is in bulk or unit dosage form. The unit dosage form may be in any of a variety of forms, including, for example, a capsule, an IV bag, a tablet, a single pump on an aerosol inhaler, or a vial. The amount of active ingredient (e.g., a formulation of the disclosed compound or a salt, hydrate, solvate, or isomer thereof) in a unit dose of the composition is an effective amount and varies depending on the specific treatment involved. Those skilled in the art will appreciate that routine variations in dosage may be necessary depending on the age and condition of the patient. The dosage also depends on the route of administration. Various routes are contemplated, including oral, pulmonary, rectal, parenteral, transdermal, subcutaneous, intravenous, intramuscular, intraperitoneal, inhalation, buccal, sublingual, intrapleural, intrathecal, intranasal, etc. Dosage forms for topical or transdermal administration of a compound of the present disclosure include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches, and inhalants. In one embodiment, the active compound is mixed under sterile conditions with a pharmaceutically acceptable carrier, and with any preservatives, buffers, or propellants that are required.

[0356] As used herein, the term "pharmaceutically acceptable" refers to compounds, anions, cations, materials, compositions, carriers, and / or dosage forms that are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit / risk ratio.

[0357] As used herein, the term "pharmaceutically acceptable excipient" means an excipient that is generally safe, non-toxic, and not biologically or otherwise undesirable and is useful in preparing pharmaceutical compositions, and includes excipients that are acceptable for veterinary and human pharmaceutical use. As used in the specification and claims, "pharmaceutically acceptable excipient" includes both one and more than one such excipient.

[0358] It should be understood that the pharmaceutical compositions of the present disclosure are formulated to be compatible with their intended route of administration. Examples of routes of administration include parenteral, e.g., intravenous, intradermal, subcutaneous, oral (e.g., inhalation), transdermal (topical), and transmucosal administration. Solutions or suspensions used for parenteral, intradermal, or subcutaneous administration may contain the following components: a sterile diluent such as water for injection, saline solution, fixed oils, polyethylene glycol, glycerin, propylene glycol, or other synthetic solvents; antibacterial agents such as benzyl alcohol and methylparaben antibacterial agents; antioxidants such as ascorbic acid and sodium bisulfite; chelating agents such as ethylenediaminetetraacetic acid; buffers such as acetates, citrates, or phosphates; and agents for adjusting tonicity such as sodium chloride or dextrose. pH can be adjusted with acids or bases, such as hydrochloric acid or sodium hydroxide. Parenteral formulations can be enclosed in ampoules, disposable syringes, or multiple-dose vials made of glass or plastic.

[0359] It should be understood that the compounds or pharmaceutical compositions of the present disclosure can be administered to a subject by many of the well-known methods currently used in chemotherapy treatment.For example, the compounds of the present disclosure can be injected into the bloodstream or body cavity, or taken orally, or applied through the skin with a patch.The selected dose should be sufficient to constitute effective treatment, but not too high to cause unacceptable side effects.It is advisable to carefully monitor the patient's condition and health status during and after treatment for a reasonable period of time.

[0360] As used herein, the term "therapeutically effective amount" refers to an amount of an agent to treat, ameliorate, or prevent a specified disease or condition, or to exhibit a detectable therapeutic or inhibitory effect. The effect can be detected by any assay method known in the art. The precise effective amount for a subject will vary depending on the subject's weight, size, and health; the nature and extent of the condition; and the therapeutic agent or combination of therapeutic agents selected for administration. The therapeutically effective amount for a given situation can be determined by routine experimentation that is within the skill and judgment of the clinician.

[0361] It should be understood that for any compound, the therapeutically effective amount can be estimated initially either in cell culture assays, for example, of tumor cells, or in animal models, usually rats, mice, rabbits, dogs, or pigs. Animal models can also be used to determine appropriate concentration ranges and routes of administration. Such information can then be used to determine doses and routes useful for administration to humans. Therapeutic / prophylactic efficacy and toxicity can be determined using standard pharmaceutical methods in cell cultures or experimental animals, for example, ED 50 (the dose therapeutically effective in 50% of the population) and LD 50 The dose ratio between toxic and therapeutic effects is the therapeutic index, and the ratio LD 50 / ED 50 Pharmaceutical compositions that exhibit large therapeutic indices are preferred. The dosage can vary within this range depending on the dosage form used, sensitivity of the patient, and the route of administration.

[0362] Dosage and administration are adjusted to provide sufficient levels of the active agent or to maintain the desired effect. Factors that may be considered include the severity of the disease state, the subject's general health, the subject's age, weight, sex, diet, time and frequency of administration, drug combinations, reaction sensitivities, and tolerance / response to treatment. Long-acting pharmaceutical compositions can be administered every 3-4 days, every week, or once every two weeks, depending on the half-life and clearance rate of the specific formulation.

[0363] The pharmaceutical composition containing the active compound of the present disclosure can be prepared by a generally known method, for example, by conventional mixing, dissolving, granulating, dragee making, wet grinding, emulsifying, encapsulating, entrapping or lyophilization.The pharmaceutical composition can be prepared by conventional methods using one or more pharmaceutically acceptable carriers, including excipients and / or adjuvants that facilitate the processing of active compound into pharmaceutically usable preparations.Of course, the appropriate formulation depends on the selected route of administration.

[0364] Pharmaceutical compositions suitable for injectable use include sterile aqueous solutions (where water soluble) or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersion. Carriers suitable for intravenous administration include physiological saline, bacteriostatic water, Cremophor EL™ (BASF, Parsippany, NJ), or phosphate-buffered saline (PBS). In all cases, the composition must be sterile and fluid to the extent that easy syringability exists. It must be stable under the conditions of manufacture and storage and must be preserved against the contaminating action of microorganisms, such as bacteria and fungi. The carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (e.g., glycerol, propylene glycol, and liquid polyethylene glycol), and suitable mixtures thereof. Proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants. Prevention of the action of microorganisms can be achieved by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, ascorbic acid, thimerosal, and the like. In many cases, it is preferable to include isotonic agents, for example, sugars, polyalcohols such as mannitol and sorbitol, and sodium chloride in the composition. Prolonged absorption of injectable compositions can be brought about by including in the composition an agent that delays absorption, for example, aluminum monostearate and gelatin.

[0365] Sterile injectable solution can be prepared by incorporating the required amount of active compound into a suitable solvent containing one or a combination of the above-listed ingredients as needed, followed by filtration sterilization.Generally, dispersion is prepared by incorporating active compound into a sterile vehicle that contains a basic dispersion medium and the other ingredients required from the above-listed ingredients.For the preparation of sterile injectable solution, the method of preparation is vacuum drying and freeze-drying, which produces a powder of active compound and additional desired ingredients from its solution that has been previously sterile-filtered.

[0366] Oral compositions generally contain an inert diluent or an edible pharmaceutically acceptable carrier. These can be enclosed in gelatin capsules or compressed into tablets. For oral therapeutic administration, the active compound can be incorporated into an excipient and used in the form of tablets, lozenges, or capsules. Oral compositions can also be prepared using a fluid carrier for use as a mouthwash, where the compound in the fluid carrier is orally applied, swished, expectorated, or swallowed. Pharmaceutically compatible binding agents and / or adjuvant materials can be included as part of the composition. The tablets, pills, capsules, troches and the like may contain any of the following ingredients, or compounds of a similar nature: a binder such as microcrystalline cellulose, gum tragacanth, or gelatin; an excipient such as starch or lactose; a disintegrant such as alginic acid, Primogel, or corn starch; a lubricant such as magnesium stearate or sterotes; a glidant such as colloidal silicon dioxide; a sweetening agent such as sucrose or saccharin; or a flavoring agent such as peppermint, methyl salicylate, or orange flavor.

[0367] For administration by inhalation, the compounds are delivered in the form of an aerosol spray from pressured container or dispenser which contains a suitable propellant, eg, a gas such as carbon dioxide, or a nebulizer.

[0368] Systemic administration can also be via transmucosal or transdermal means. For transmucosal or transdermal administration, a penetrant appropriate to the barrier to be permeated is used in the formulation. Such penetrants are generally known in the art, and include, for example, for transmucosal administration, surfactants, bile salts, and fusidic acid derivatives. Transmucosal administration can be carried out using nasal sprays or suppositories. For transdermal administration, the active compound is formulated into ointments, salves, gels, or creams, as generally known in the art.

[0369] The active compounds can be prepared with pharmaceutically acceptable carriers that protect the compound against rapid elimination from the body, such as controlled-release formulations, including implants and microencapsulated delivery systems. Biodegradable, biocompatible polymers, such as ethylene vinyl acetate, polyanhydrides, polyglycolic acid, collagen, polyorthoesters, and polylactic acid, can be used. Methods for preparing such formulations will be apparent to those skilled in the art. Materials are also commercially available from Alza Corporation and Nova Pharmaceuticals, Inc. Liposomal suspensions (including liposomes targeted to infected cells with monoclonal antibodies against viral antigens) can also be used as pharmaceutically acceptable carriers. These can be prepared according to methods known to those skilled in the art, for example, as described in U.S. Pat. No. 4,522,811.

[0370] For ease of administration and uniformity of dosage, it is particularly advantageous to formulate oral or parenteral compositions into dosage unit form.As used herein, dosage unit refers to a physically separate unit suitable as a unit dose of the subject to be treated.Each unit contains a predetermined amount of active compound calculated to produce desired therapeutic effect in association with necessary pharmaceutical carrier.The specification of dosage unit form of the present disclosure is determined by and directly depends on the characteristics of active compound and the specific therapeutic effect to be achieved.

[0371] In therapeutic applications, dosages of pharmaceutical compositions used in accordance with the present disclosure will vary depending on the agent, the age, weight, and clinical condition of the recipient patient, and the experience and judgment of the clinician or practitioner administering the treatment, among other factors that will influence the selected dosage. Generally, the dosage should be sufficient to slow, preferably regress, symptoms of the disease, and preferably cause complete regression of the disease. Doses can range from about 0.01 mg / kg per day to about 5000 mg / kg per day. In preferred embodiments, dosages can range from about 1 mg / kg per day to about 1000 mg / kg per day. In certain embodiments, the dose may range from about 0.1 mg / day to about 50 g / day; from about 0.1 mg / day to about 25 g / day; from about 0.1 mg / day to about 10 g / day; from about 0.1 mg / day to about 3 g / day; or from about 0.1 mg to about 1 g / day, and may be administered in single, divided, or continuous doses (this dose is determined based on the patient's weight (kg), body surface area (m)). 2 ), and age (years). An effective amount of a drug is that amount that provides an objectively identifiable improvement as noted by a clinician or other qualified observer. Improved survival and growth indicate regression. As used herein, the term "dosage-effective manner" refers to the amount of an active compound to produce a desired biological effect in a subject or cell.

[0372] It should be appreciated that the pharmaceutical compositions can be included in a container, pack, or dispenser together with instructions for administration.

[0373] For compounds of the present disclosure that are capable of further forming salts, it should be understood that all of these forms are also contemplated within the scope of the claimed disclosure.

[0374] As used herein, the term "pharmaceutically acceptable salt" refers to a derivative of a compound of the present disclosure, in which the parent compound is modified by making an acid or base salt thereof. In some embodiments, a pharmaceutically acceptable salt of a compound (e.g., a β-lactam compound described herein or probenecid) is also a prodrug of the compound. Examples of pharmaceutically acceptable salts include, but are not limited to, inorganic or organic acid salts of basic residues such as amines, alkali or organic salts of acidic residues such as carboxylic acids, and the like. Pharmaceutically acceptable salts include conventional non-toxic salts or quaternary ammonium salts of the parent compound formed, for example, from non-toxic inorganic or organic acids. For example, such conventional non-toxic salts include, but are not limited to, 2-acetoxybenzoic acid, 2-hydroxyethanesulfonic acid, acetic acid, ascorbic acid, benzenesulfonic acid, benzoic acid, bicarbonate, carbonic acid, citric acid, edetic acid, ethanedisulfonic acid, 1,2-ethanesulfonic acid, fumaric acid, glucoheptonic acid, gluconic acid, glutamic acid, glycolic acid, glycolarsanilic acid, hexylresorcylic acid, hydrabamic acid, hydrobromic acid, hydrochloric acid, hydroiodic acid, hydroxymaleic acid, hydroxynaphthoic acid, isethionic acid, and the like. These include those derived from inorganic and organic acids selected from acetic acid, lactic acid, lactobionic acid, laurylsulfonic acid, maleic acid, malic acid, mandelic acid, methanesulfonic acid, napsylic acid, nitric acid, oxalic acid, pamoic acid, pantothenic acid, phenylacetic acid, phosphoric acid, polygalacturonic acid, propionic acid, salicylic acid, stearic acid, acetic acid, succinic acid, sulfamic acid, sulfanilic acid, sulfuric acid, tannic acid, tartaric acid, toluenesulfonic acid, and commonly occurring amino acids such as glycine, alanine, phenylalanine, arginine, etc.

[0375] Other examples of pharmaceutically acceptable salts include hexanoic acid, cyclopentanepropionic acid, pyruvic acid, malonic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, 4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, 4-toluenesulfonic acid, camphorsulfonic acid, 4-methylbicyclo-[2.2.2]-oct-2-ene-1-carboxylic acid, 3-phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid, muconic acid, etc. The present disclosure also encompasses salts formed when an acidic proton present in the parent compound is replaced by a metal ion, e.g., an alkali metal ion, alkaline earth ion, or aluminum ion, or coordinates with an organic base, e.g., ethanolamine, diethanolamine, triethanolamine, tromethamine, N-methylglucamine, etc. It should be understood that in the salt form, the ratio of the compound to the cation or anion of the salt can be 1:1, or any ratio other than 1:1, for example, 3:1, 2:1, or 1:2.

[0376] It should be understood that all references to pharmaceutically acceptable salts include the solvent addition forms (solvates) or crystal forms (polymorphs) as defined herein of the same salt.

[0377] As used herein, the term "prodrug" refers to any agent that, when administered to a mammal, is converted in whole or in part to a target compound (e.g., a β-lactam compound described herein or probenecid). In some embodiments, a prodrug of a compound (e.g., a β-lactam compound described herein or probenecid) is also a pharmaceutically acceptable salt of the compound.

[0378] It should be understood that the compounds of the present disclosure can also be prepared as esters, for example, pharmaceutically acceptable esters. For example, a carboxylic acid functional group in a compound can be converted to its corresponding ester, for example, a methyl, ethyl, or other ester. Also, an alcohol group in a compound can be converted to its corresponding ester, for example, an acetate, propionate, or other ester.

[0379] The compound or its pharmaceutically acceptable salt may be administered orally, nasally, transdermally, pulmonary, inhalation, buccal, sublingually, intraperitoneally, subcutaneously, intramuscularly, intravenously, rectally, intrapleurally, intrathecally, and parenterally. In one embodiment, the compound is administered orally. Those skilled in the art will recognize the advantages of certain administration routes.

[0380] The dosage regimen utilizing the compound is selected according to a variety of factors, including the type, species, age, weight, sex, and condition of the patient; the severity of the condition being treated; the route of administration; the patient's renal and hepatic function; and the particular compound or salt thereof being used. An ordinarily skilled physician or veterinarian can readily determine and prescribe the effective amount of the drug required to prevent, counter, or arrest the progress of the condition.

[0381] Techniques for formulating and administering the disclosed compounds of the present disclosure can be found in Remington: the Science and Practice of Pharmacy, 19th edition, Mack Publishing Co., Easton, PA (1995). In one embodiment, the compounds described herein and their pharmaceutically acceptable salts are used in pharmaceutical preparations in combination with a pharmaceutically acceptable carrier or diluent. Suitable pharmaceutically acceptable carriers include inert solid fillers or diluents, and sterile aqueous or organic solutions. The compounds will be present in such pharmaceutical compositions in an amount sufficient to provide the desired dosage in the range described herein.

[0382] All percentages and ratios used herein are by weight unless otherwise indicated. Other features and advantages of the present disclosure will be apparent from the different examples. The examples provided illustrate different components and methodologies useful in implementing the present disclosure. The examples do not limit the claimed disclosure. Based on the present disclosure, one skilled in the art will be able to identify and use other components and methods useful in implementing the present disclosure.

[0383] In the synthetic schemes described herein, compounds may be depicted in one particular configuration for simplicity. Such a particular configuration should not be construed to limit the disclosure to one or another isomer, tautomer, positional isomer, or stereoisomer, nor does it exclude mixtures of isomers, tautomers, positional isomers, or stereoisomers. However, it will be understood that a given isomer, tautomer, positional isomer, or stereoisomer may have a higher level of activity than another isomer, tautomer, positional isomer, or stereoisomer.

[0384] Once compounds designed, selected, and / or optimized by the above methods are produced, they can be characterized using a variety of assays known to those of skill in the art to determine whether the compounds have biological activity. For example, molecules can be characterized by conventional assays, including but not limited to, the assays described below, to determine whether they have the expected activity, binding activity, and / or binding specificity.

[0385] Furthermore, high-throughput screening can be used to speed up analysis using such assays. As a result, it is possible to rapidly screen the activity of the molecules described herein using techniques known in the art. General methodologies for performing high-throughput screening are described, for example, in Devlin (1998) High Throughput Screening, Marcel Dekker, and U.S. Patent No. 5,763,263. High-throughput assays can use one or more different assay techniques, including, but not limited to, those described below.

[0386] All publications and patent documents cited herein are incorporated by reference as if each such publication or document was specifically and individually indicated to be incorporated by reference herein. Citation of publications and patent documents is not intended as an admission that any is pertinent prior art, nor does it constitute an admission as to the contents or date thereof. While the invention has been described herein by way of a written description, those skilled in the art will recognize that the invention can be practiced in various embodiments, and that the foregoing description and the following examples are intended to be illustrative, and not limiting, of the scope of the claims which follow. [Example]

[0387] Example 1. Effect of sulopenem and sulopenem etzadroxil on the administration of valproic acid In Cohort 1, multiple doses of intravenous sulopenem (1,000 mg infused over 3 hours) were administered to assess the effect of valproic acid from time 0 to the administration period (AUC 0-tau ) and the area under the plasma concentration-time curve extrapolated to the maximum observed plasma concentration (C maxSS ) were reduced by approximately 33% and 28%, respectively, compared with administration of valproic acid alone. Coadministration of valproic acid and sulopenem etzadroxil (500 mg) without probenecid reduced the AUC of valproic acid compared with administration of valproic acid alone. 0-tau and C maxSS were reduced by approximately 25% and 19%, respectively (Tables 1-3 and Figures 1-2). In contrast, AUC 0-tau and C maxSS The 90% confidence intervals (CIs) of the geometric mean ratio (GMR) of valproic acid and the bilayer tablet relative to valproic acid alone were within the range of 80-125% of the standard values ​​used to demonstrate bioequivalence. [Table 1] [Table 2] [Table 3]

[0388] Example 2. Effect of probenecid on valproic acid bioavailability during administration of valproic acid and sulopenem etzadroxil In cohorts 2 and 3, all patients received daily valproic acid. Starting on day 5, cohort 3 received sulopenem etzadroxil tablets ("etzadroxil tablets") alone, and cohort 2 received sulopenem etzadroxil and probenecid bilayer tablets (500 mg sulopenem etzadroxil + 500 mg probenecid film-coated bilayer tablets; "bilayer tablets"). The effect of dosing on valproic acid bioavailability is shown in Figure 3 and Tables 4-6. After a single oral dose of sulopenem (bilayer tablets or etzadroxil tablets), the maximum observed plasma concentrations (t max The median time to achieve valproic acid bioavailability was 2,000 hours. Sulopenem etzadroxil / probenecid bilayer tablets did not affect the steady-state pharmacokinetic profile of valproic acid in healthy adult male subjects, whereas multiple doses of intravenous sulopenem or sulopenem etzadroxil tablets had a weak effect. These findings confirm that the effect of probenecid on valproic acid bioavailability can occur as early as 3 days.

[0389] Overall, valproic acid and sulopenem were well tolerated and safe in all formulations. The most common drug-related treatment-emergent adverse events (TEAEs) were mild diarrhea and abnormal urine odor. There were no deaths or serious adverse events (SAEs). No clinically meaningful changes in vital signs, 12-lead electrocardiograms, physical examinations, or clinical laboratory parameters were reported in this study. [Table 4] [Table 5-1] [Table 5-2] [Table 6-1] [Table 6-2]

[0390] Example 3. Effect of probenecid on sulopenem bioavailability during administration of valproic acid and sulopenem etzadroxil In Cohorts 2 and 3, all patients received daily valproic acid. Starting on Day 5, Cohort 3 received sulopenem etzadroxil tablets ("etzadroxil tablets") alone, while Cohort 2 received sulopenem etzadroxil and probenecid bilayer tablets (500 mg sulopenem etzadroxil + 500 mg probenecid film-coated bilayer tablets; "bilayer tablets"). The effect of dosing on sulopenem bioavailability is shown in Tables 7-10. Comparing Tables 7 and 9 demonstrates the enhancement of sulopenem pharmacokinetic parameters with bilayer tablets after 5 days of administration. Comparing Tables 8 and 10 demonstrates the enhancement of sulopenem pharmacokinetic parameters with bilayer tablets after 7 days of administration. [Table 7] [Table 8] [Table 9] [Table 10-1] [Table 10-2]

[0391] equivalent It should be understood that the present invention may be embodied in other specific forms without departing from its spirit or essential characteristics. The foregoing embodiments are therefore to be considered in all respects as illustrative and not limiting of the invention described herein. The scope of the invention is, therefore, indicated by the appended claims rather than the foregoing description, and all changes that come within the meaning and range of equivalency of the claims are intended to be embraced therein.

Claims

1. 1. A combination drug for use in treating or preventing a disease, comprising: the disease is an uncomplicated urinary tract infection, a complicated urinary tract infection, a complicated intra-abdominal infection, an uncomplicated intra-abdominal infection, pneumonia, otitis media, sinusitis, gonococcal urethritis, pelvic inflammatory disease, prostatitis, a bone infection, a joint infection, a diabetic foot infection, or infectious diarrhea; wherein said use comprises administering said combination drug to a subject in need thereof; The combination drug may be: a pharmaceutically effective amount of valproic acid or a pharmaceutically acceptable salt thereof; a pharmaceutically effective amount of a β-lactam compound or a pharmaceutically acceptable salt thereof, and a pharmaceutically effective amount of probenecid or a pharmaceutically acceptable salt thereof; Including, The β-lactam compound is compound (III-2): 【Chemistry 1】 or a pharmaceutically acceptable salt thereof.

2. 10. The combination of claim 1, wherein said administration reduces or alleviates side effects.

3. 3. The combination of claim 2, wherein the side effects are mania, migraine-associated mania, seizures, and increased likelihood of seizures.

4. 4. The combination of any one of claims 1 to 3, wherein the administration results in an elevated concentration of valproic acid in the subject compared to a comparable subject being administered without probenecid or a pharmaceutically acceptable salt thereof.

5. The β-lactam compound 【Chemistry 2】 The combination drug according to any one of claims 1 to 4, which is a pharmaceutically acceptable salt thereof.

6. 6. The combination of any one of claims 1 to 5, wherein the pharmaceutical salt of valproic acid is a sodium salt, potassium salt, lithium salt, ammonium salt, calcium salt, magnesium salt, iron salt, zinc salt, copper salt, manganese salt, or aluminum salt.

7. The combination of any one of claims 1 to 6, wherein the valproic acid or a pharmaceutically acceptable salt thereof is administered orally.

8. the β-lactam compound or a pharmaceutically acceptable salt thereof is orally administered; and The combination of any one of claims 1 to 7, wherein the probenecid or a pharmaceutically acceptable salt thereof is administered orally.

9. The combination according to any one of claims 1 to 8, wherein the β-lactam compound or a pharmaceutically acceptable salt thereof and probenecid or a pharmaceutically acceptable salt thereof are administered simultaneously, sequentially, or alternately.

10. The combination of any one of claims 1 to 9, wherein the β-lactam compound or a pharmaceutically acceptable salt thereof and probenecid or a pharmaceutically acceptable salt thereof are administered simultaneously.

11. The combination according to any one of claims 1 to 10, wherein the valproic acid or a pharmaceutically acceptable salt thereof, the β-lactam compound or a pharmaceutically acceptable salt thereof, and probenecid or a pharmaceutically acceptable salt thereof are administered by the same route.

12. 12. The combination of any one of claims 1 to 11, wherein the valproic acid or a pharmaceutically acceptable salt thereof, the β-lactam compound or a pharmaceutically acceptable salt thereof, and the probenecid or a pharmaceutically acceptable salt thereof are administered orally.

13. 13. The combination of any one of claims 1 to 12, wherein an oral co-formulation comprising the β-lactam compound or a pharmaceutically acceptable salt thereof and probenecid or a pharmaceutically acceptable salt thereof is administered.

14. The combination of any one of claims 1 to 13, wherein a tablet containing the β-lactam compound or a pharmaceutically acceptable salt thereof and probenecid or a pharmaceutically acceptable salt thereof is administered.

15. 15. The combination of claim 14, wherein the tablet is a bilayer tablet comprising a second layer comprising a β-lactam compound or a pharmaceutically acceptable salt thereof and a first layer comprising probenecid or a pharmaceutically acceptable salt thereof.

16. the first layer comprises 20 mg to about 5 g, about 50 mg to about 2 g, about 80 mg to about 1 g, about 100 mg to about 900 mg, about 200 mg to about 800 mg, about 300 mg to about 700 mg, about 400 mg to about 600 mg, about 450 mg to about 550 mg, or about 480 mg to about 520 mg of probenecid or a pharmaceutically acceptable salt thereof; and 16. The combination of claim 15, wherein the second layer comprises 20 mg to about 5 g, about 50 mg to about 2 g, about 80 mg to about 1 g, about 100 mg to about 900 mg, about 200 mg to about 800 mg, about 300 mg to about 700 mg, about 400 mg to about 600 mg, about 450 mg to about 550 mg, or about 480 mg to about 520 mg of a β-lactam compound or a pharmaceutically acceptable salt thereof.

17. 17. The combination of any one of claims 15-16, wherein the first layer comprises about 500±450 mg, about 500±400 mg, about 500±350 mg, about 500±300 mg, about 500±250 mg, about 500±200 mg, about 500±150 mg, about 500±100 mg, about 500±90 mg, about 500±80 mg, about 500±70 mg, about 500±60 mg, about 500±50 mg, about 500±45 mg, about 500±40 mg, about 500±35 mg, about 500±30 mg, about 500±25 mg, about 500±20 mg, about 500±15 mg, about 500±10 mg, or about 500±5 mg of probenecid or a pharmaceutically acceptable salt thereof.

18. 18. The combination of any one of claims 15 to 17, wherein the second layer comprises about 500±400 mg, about 500±350 mg, about 500±300 mg, about 500±250 mg, about 500±200 mg, about 500±150 mg, about 500±100 mg, about 500±90 mg, about 500±80 mg, about 500±70 mg, about 500±60 mg, about 500±50 mg, about 500±45 mg, about 500±40 mg, about 500±35 mg, about 500±30 mg, about 500±25 mg, about 500±20 mg, about 500±15 mg, about 500±10 mg, or about 500±5 mg of a β-lactam compound or a pharmaceutically acceptable salt thereof.

19. 19. The combination of any one of claims 1 to 18, wherein the valproic acid or a pharmaceutically acceptable salt thereof is administered at a dose of about 50 mg / day, about 100 mg / day, about 150 mg / day, about 200 mg / day, about 250 mg / day, about 300 mg / day, about 350 mg / day, about 400 mg / day, about 500 mg / day, about 1 g / day, about 2 g / day, about 3 g / day, about 4 g / day, or about 5 g / day.

20. 20. The combination of any one of claims 1 to 19, wherein the β-lactam compound or a pharmaceutically acceptable salt thereof is administered at a dose of about 50 mg / day, about 100 mg / day, about 150 mg / day, about 200 mg / day, about 250 mg / day, about 300 mg / day, about 350 mg / day, about 400 mg / day, about 500 mg / day, about 1 g / day, about 2 g / day, about 3 g / day, about 4 g / day, or about 5 g / day.

21. 21. The combination of any one of claims 1 to 20, wherein the probenecid or a pharmaceutically acceptable salt thereof is administered at a dose of about 50 mg / day, about 100 mg / day, about 150 mg / day, about 200 mg / day, about 250 mg / day, about 300 mg / day, about 350 mg / day, about 400 mg / day, about 500 mg / day, about 1 g / day, about 2 g / day, about 3 g / day, about 4 g / day, or about 5 g / day.

22. the valproic acid or a pharmaceutically acceptable salt thereof is administered at a dose of 500±300 mg / day, 500±250 mg / day, 500±200 mg / day, 500±150 mg / day, 500±100 mg / day, 500±90 mg / day, 500±80 mg / day, 500±70 mg / day, 500±60 mg / day, 500±50 mg / day, 500±40 mg / day, 500±30 mg / day, 500±20 mg / day, 500±10 mg / day, 500±5 mg / day, 500±4 mg / day, 500±3 mg / day, 500±2 mg / day, or 500±1 mg / day; the beta-lactam compound or a pharmaceutically acceptable salt thereof is administered at a dose of 500±300 mg / day, 500±250 mg / day, 500±200 mg / day, 500±150 mg / day, 500±100 mg / day, 500±90 mg / day, 500±80 mg / day, 500±70 mg / day, 500±60 mg / day, 500±50 mg / day, 500±40 mg / day, 500±30 mg / day, 500±20 mg / day, 500±10 mg / day, 500±5 mg / day, 500±4 mg / day, 500±3 mg / day, 500±2 mg / day, or 500±1 mg / day; and the probenecid or pharmaceutically acceptable salt thereof is administered at a dose of 500±300 mg / day, 500±250 mg / day, 500±200 mg / day, 500±150 mg / day, 500±100 mg / day, 500±90 mg / day, 500±80 mg / day, 500±70 mg / day, 500±60 mg / day, 500±50 mg / day, 500±40 mg / day, 500±30 mg / day, 500±20 mg / day, 500±10 mg / day, 500±5 mg / day, 500±4 mg / day, 500±3 mg / day, 500±2 mg / day, or 500±1 mg / day; A combination drug according to any one of claims 1 to 21. Combination drugs, including 23. A pharmaceutical composition for use in treating or preventing a disease, comprising: the disease is an uncomplicated urinary tract infection, a complicated urinary tract infection, a complicated intra-abdominal infection, an uncomplicated intra-abdominal infection, pneumonia, otitis media, sinusitis, gonococcal urethritis, pelvic inflammatory disease, prostatitis, a bone infection, a joint infection, a diabetic foot infection, or infectious diarrhea; wherein said use comprises administering said pharmaceutical composition to a subject in need thereof; The pharmaceutical composition comprises: a pharmaceutically effective amount of valproic acid or a pharmaceutically acceptable salt thereof; a pharmaceutically effective amount of a β-lactam compound or a pharmaceutically acceptable salt thereof, and a pharmaceutically effective amount of probenecid or a pharmaceutically acceptable salt thereof; Including, The β-lactam compound is compound (III-2): 【Transformation 3】 or a pharmaceutically acceptable salt thereof.

24. A pharmaceutical kit for use in treating or preventing a disease, comprising: the disease is an uncomplicated urinary tract infection, a complicated urinary tract infection, a complicated intra-abdominal infection, an uncomplicated intra-abdominal infection, pneumonia, otitis media, sinusitis, gonococcal urethritis, pelvic inflammatory disease, prostatitis, a bone infection, a joint infection, a diabetic foot infection, or infectious diarrhea; wherein said use comprises administering said pharmaceutical kit to a subject in need thereof; The pharmaceutical kit comprises: a pharmaceutically effective amount of valproic acid or a pharmaceutically acceptable salt thereof; a pharmaceutically effective amount of a β-lactam compound or a pharmaceutically acceptable salt thereof, and a pharmaceutically effective amount of probenecid or a pharmaceutically acceptable salt thereof Including, The β-lactam compound is compound (III-2): 【Chemistry 4】 or a pharmaceutically acceptable salt thereof.

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